Substituted pyrimidines for treating bacterial infections

ABSTRACT

The present teachings relate to hydroxypyrimidinone derivatives of Formula II, pharmaceutical compositions thereof, and methods of using such compounds to treat bacterial infections.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 15/773,975,filed May 4, 2018, which was filed as a 371 U.S. National Stage ofInternational Application No. PCT/US2016/061195, on Nov. 9, 2016, whichclaims the benefit of U.S. Application Ser. No. 62/252,795, filed Nov.9, 2015, each of which are hereby incorporated by reference in theirentirety.

BACKGROUND OF THE INVENTION

Metalloproteins influence a vast diversity of biological systems,biological processes, and diseases. For example,UDP-{3-O—[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase(LpxC) is an essential enzyme involved in the first committed step inlipid A biosynthesis for gram-negative bacteria. Lipid A is an essentialcomponent of the outer membrane of Gram-negative bacteria. LpxC is azinc(II)-dependent metalloenzyme, with two histidines and an asparticacid residue bound to the zinc(II) ion. Structures of LpxC show thezinc(II) ion is bound to two water molecules, both of which have beenimplicated in the mechanism of the enzyme. LpxC is highly conservedacross strains of Gram-negative bacteria. This makes LpxC an attractivetarget to treat Gram-negative infections.

Many LpxC inhibitors developed to date have issues including lack ofcell permeability, off-target toxicity, and efflux.

In recent years, there has been an increase in resistant and multi-drugresistant strains of bacteria. Thus, there is a need for newantibiotics, especially with new mechanisms of action. There remains aneed for metalloprotein modulators of LpxC useful in the field oftherapeutics, diagnostics, and research.

SUMMARY OF THE INVENTION

Some embodiments provided herein describe compounds and compositionsuseful for treating bacterial infections.

In one aspect, provided herein are compounds having the structure ofFormula II:

or a pharmaceutically acceptable salt thereof,

-   -   wherein:    -   R₁ is H, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₃ is —OH, —NH₂, or SH;    -   Z is O or S;    -   L₁ is a bivalent radical selected from a bond, —C(═O)—,        —(C(═O)O)—, —(C(═O)NR^(b))—, —N(R^(b))C(═O)—, —(C₁₋₄        alkylene)-O—, —(C₁₋₄ alkylene)-N(R^(b))—, —(C₁₋₄ alkylene)-S—,        or —(C₁₋₄ alkylene)-S(═O)₂—;    -   L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-(C(═O)NR⁵)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-O—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-S(═O)₂—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-S(═O)₂N(R₅)—, or —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)S(═O)₂—;    -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ alkenyl, an optionally        substituted C₁₋₆ alkynyl, an optionally substituted C₆₋₁₄ aryl,        an optionally substituted 5- to 14-membered heteroaryl, an        optionally substituted C₃-C₈ cycloalkyl, on optionally        substituted —(C₀₋₄ alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄        alkene), —(C₀₋₄ alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle,        —(C₀₋₄ alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H,        —(C₀₋₄ alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted heteroalkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl or an optionally substituted alkoxy;    -   L₃ is a bivalent radical selected from —(C₂₋₆ alkenylene)- or        —(C₂₋₆ alkynylene)-;    -   L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,        —(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;    -   G₁ and G₂ are each independently, at each occurrence, a bivalent        radical selected from —(C₆₋₁₄ arylene)- or -(5- to 14-membered        heteroarylene)-;    -   G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5-        to 14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄        heteroalkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ heteroalkyl), an optionally        substituted alkyl, an optionally substituted heteroalkyl, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted heterocyclyl, an optionally substituted aryl, an        optionally substituted heteroaryl or an optionally substituted        alkoxy;    -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl; and    -   n is 1 or 2.

In one embodiment,

-   -   R₁ is H or C₁₋₆ alkyl;    -   R₂ is H, —OR^(a), C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₃ is —OH;    -   Z is O;    -   L₁ is a bivalent radical selected from a bond, —C(═O)—,        —(C(═O)O)—, —(C(═O)NR^(b))—, —N(R^(b))C(═O)—, —(C₁₋₄        alkylene)-N(R^(b))—, or —(C₁₋₄ alkylene)-S(═O)₂—;    -   L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-(C(═O)NR⁵)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-O—, or        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—;    -   wherein each R₄ is H or C₁₋₆ alkyl; and    -   each R₅ is independently H, C₁₋₆ alkyl, —(C₁₋₄ alkylene)-OR^(d),        —(C₁₋₄ alkylene)-N(R^(d))₂, or —(C₁₋₄ alkylene)-S(═O)₂—(R^(d));    -   L₃ is a bivalent radical —(C₁₋₆ alkynylene)-;    -   L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,        —(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;    -   G₁ and G₂ are each independently, at each occurrence, a bivalent        radical selected from —(C₆ arylene)- or -(5- to 6-membered        heteroarylene)-;

G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), an optionally substituted alkyl, an optionally substitutedheteroalkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl or an optionally substituted alkoxy;

-   -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl; and    -   n is 1 or 2.

In another embodiment,

-   -   R₁ is H or C₁₋₆ alkyl;    -   R₂ is H or C₁₋₆ alkyl;    -   R₃ is —OH;    -   Z is O;    -   L₁ is a bivalent radical selected from a bond, —C(═O)—,        —(C(═O)O)—, —(C(═O)NR^(b))—, or —N(R^(b))C(═O)—;    -   L₂ is a bivalent radical —(C(R₄)(R₅))_(n)(C₀₋₃ alkylene)-;    -   wherein each R₄ is H or C₁₋₆ alkyl; and    -   each R₅ independently is H, or C₁₋₆ alkyl;    -   L₃ is a bivalent radical —(C₁₋₆ alkynylene)-;    -   L₄ is a bivalent radical selected from —C(═O)— or —(C₁₋₄        alkylene)-;    -   G₁ and G₂ are each independently, at each occurrence, a bivalent        radical selected from —(C₆ arylene)- or -(5- to 6-membered        heteroarylene)-;

G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), an optionally substituted alkyl, an optionally substitutedheteroalkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl or an optionally substituted alkoxy;

-   -   R^(b) is H or C₁₋₆ alkyl; and    -   n is 1.

In another embodiment,

-   -   L₁ bivalent radical selected from a bond, —(C₁₋₄ alkylene)-O—,        —(C₁₋₄ alkylene)-N(R^(b))—, —(C₁₋₄ alkylene)-S—, or —(C₁₋₄        alkylene)-S(═O)₂—;    -   R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy; and    -   R^(b) is H or C₁₋₆ alkyl.

In another embodiment, R₅ is —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄ alkylene)-(5- to 14-memberedheteroaryl).

In another aspect, one embodiment provided herein describes compoundshaving the structure of Formula IV:

or a pharmaceutically acceptable salt thereof,

-   -   wherein:    -   R₁ is H or C₁₋₆ alkyl;    -   R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   L₁ is a bivalent radical selected from a bond, —C(═O)—,        —(C(═O)O)—, —OC(═O)—, —(C(═O)NR^(b))—, —N(R^(b))C(═O)—,        —N(R^(b))—, —S(═O)₂—, —(C₁₋₄ alkylene)-, —(C₁₋₄ alkylene)-O—,        —(C₁₋₄ alkylene)-N(R^(b))—, —(C₁₋₄ alkylene)-S—, or —(C₁₋₄        alkylene)-S(═O)₂—;    -   L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-(C(═O)NR₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-O—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-S(═O)₂—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-S(═O)₂N(R₅)—, or —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)S(═O)₂—;    -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl, on optionally substituted —(C₀₋₄        alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene), —(C₀₋₄        alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄        alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄        alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted heteroalkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl or an optionally substituted alkoxy;

L₃ is a bivalent radical selected from —(C₂₋₆ alkenylene)- or —(C₂₋₆alkynylene)-;

-   -   L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,        —(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;    -   G₁ and G₂ are each independently, at each occurrence, a bivalent        radical selected from —(C₆₋₁₄ arylene)- or -(5- to 14-membered        heteroarylene)-;    -   G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, (C₁₋₄        alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄        alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ heteroalkyl), an        optionally substituted alkyl, an optionally substituted        heteroalkyl, an optionally substituted alkenyl, an optionally        substituted alkynyl, an optionally substituted cycloalkyl, an        optionally substituted heterocyclyl, an optionally substituted        aryl, an optionally substituted heteroaryl or an optionally        substituted alkoxy; and    -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl; and    -   n is 1 or 2.

In one embodiment,

-   -   R₁ is H or C₁₋₆ alkyl;    -   R₂ is H or C₁₋₆ alkyl;    -   L₁ is a bivalent radical selected from a bond, —(C(═O)O)—,        —(C(═O)NR^(b))—, —N(R^(b))C(═O)—, a bond, —(C₁₋₄ alkylene)-O—,        —(C₁₋₄ alkylene)-N(R^(b))—, or —(C₁₋₄ alkylene)-S(═O)₂—;    -   L₂ is a bivalent radical is selected from —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene), or —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—;    -   wherein each R₄ is H or an optionally substituted C₁₋₆ alkyl;        and    -   each R₅ is H or C₁₋₆ alkyl, —C(═O)NR^(b)R^(f) or —(C₁₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein R^(f) is H, an optionally substituted C₁₋₆ alkyl, an        optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl;    -   L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,        —(C(═O)NR^(c))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;    -   G₁ and G₂ are each independently, at each occurrence, a bivalent        radical selected from —(C₆₋₁₄ arylene)- or -(5- to 14-membered        heteroarylene)-;    -   G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5-        to 14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄        heteroalkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ heteroalkyl), an optionally        substituted alkyl, an optionally substituted heteroalkyl, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted heterocyclyl, or an optionally substituted alkoxy;        and    -   R^(b) and R^(e) are each independently, at each occurrence, H or        C₁₋₆ alkyl; and    -   n is 1 or 2.

In another embodiment, L₁ bivalent radical selected from a bond, —(C₁₋₄alkylene)-O—, —(C₁₋₄ alkylene)-N(R^(b))—, —(C₁₋₄ alkylene)-S—, or —(C₁₋₄alkylene)-S(═O)₂—; R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆alkoxy; and R^(b) is H or C₁₋₆ alkyl.

In another embodiment, each R₅ is independently —(C₁₋₄ alkylene)-OR^(d),—(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered heteroaryl),—C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f);

-   -   wherein R^(f) is H, an optionally substituted alkyl, an        optionally substituted heteroalkyl, an optionally substituted        cycloalkyl or an optionally substituted heterocyclyl.

Another embodiment provided herein describes a compound having thestructure of Formula IVA:

or a pharmaceutically acceptable salt thereof.

In one embodiment,

-   -   L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-O—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂—;    -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl, on optionally substituted —(C₀₋₄        alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene), —(C₀₋₄        alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄        alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄        alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted cycloalkyl, an optionally        substituted heterocyclyl, or an optionally substituted alkoxy;    -   L₃ is —(C₂₋₆ alkynylene)-;    -   L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,        —(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;    -   G₁ and G₂ are each independently, at each occurrence, —(C₆₋₁₄        arylene)-;    -   G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5-        to 14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄        heteroalkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ heteroalkyl), an optionally        substituted alkyl, an optionally substituted heteroalkyl, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted heterocyclyl, or an optionally substituted alkoxy;        and    -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl; and    -   n is 1 or 2.

In another embodiment,

-   -   L₂ is —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂—;    -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl, on optionally substituted —(C₀₋₄        alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene), —(C₀₋₄        alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄        alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄        alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted cycloalkyl, an optionally        substituted heterocyclyl, or an optionally substituted alkoxy;    -   L₃ is —(C₂₋₆ alkynylene)-;    -   L₄ is —C(═O)—, —(C(═O)O)—, —(C(═O)NR^(e))—, or —(C₁₋₄        alkylene)-;    -   G₁ and G₂ are each independently, at each occurrence, —(C₆₋₁₄        arylene)-;    -   G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5-        to 14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄        heteroalkyl), (C₁₋₄ alkylene)-(C₁₋₄ heterocycloalkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀        heterocycloalkylene)-(C₃₋₁₀ heterocycloalkyl), C₁₋₆ alkyl, or        (C₃₋₁₀ heterocycloalkylene)-hydroxy; and    -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl; and    -   n is 1 or 2.

In yet another embodiment, G₃ is H, C₃₋₁₀ heterocycloalkyl, (C₁₋₄alkylene)-(C₁₋₄ heteroalkyl), (C₁₋₄ alkylene)-(C₁₋₄ heterocycloalkyl),(C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₃₋₁₀ heterocycloalkyl), C₁₋₆ alkyl, (C₃₋₁₀heterocycloalkylene)-hydroxy, or tetrazolyl.

Also provided herein in one embodiment is a compound having thestructure of Formula IVB:

or a pharmaceutically acceptable salt thereof.

In another embodiment,

-   -   L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-O—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂—;    -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl, on optionally substituted —(C₀₋₄        alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene), —(C₀₋₄        alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄        alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄        alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted cycloalkyl, an optionally        substituted heterocyclyl, or an optionally substituted alkoxy;    -   L₃ is —(C₂₋₆ alkynylene)-;    -   L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,        —(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;    -   G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5-        to 14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄        heteroalkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ heteroalkyl), an optionally        substituted alkyl, an optionally substituted heteroalkyl, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted heterocyclyl, or an optionally substituted alkoxy;        and    -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl; and    -   n is 1 or 2.

In another embodiment,

-   -   L₂ is —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂—;    -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl, on optionally substituted —(C₀₋₄        alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene), —(C₀₋₄        alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄        alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄        alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted cycloalkyl, an optionally        substituted heterocyclyl, or an optionally substituted alkoxy;    -   L₃ is —(C₂₋₆ alkynylene)-;    -   L₄ is —C(═O)—, —(C(═O)O)—, —(C(═O)NR^(e))—, or —(C₁₋₄        alkylene)-;    -   G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5-        to 14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄        heteroalkyl), (C₁₋₄ alkylene)-(C₁₋₄ heterocycloalkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀        heterocycloalkylene)-(C₃₋₁₀ heterocycloalkyl), C₁₋₆ alkyl, or        (C₃₋₁₀ heterocycloalkylene)-hydroxy; and

R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at eachoccurrence, H or C₁₋₆ alkyl; and

-   -   n is 1 or 2.

In another embodiment, G₃ is H, C₃₋₁₀ heterocycloalkyl, (C₁₋₄alkylene)-(C₁₋₄ heteroalkyl), (C₁₋₄ alkylene)-(C₁₋₄ heterocycloalkyl),(C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₃₋₁₀ heterocycloalkyl), C₁₋₆ alkyl, (C₃₋₁₀heterocycloalkylene)-hydroxy, or tetrazolyl.

In another aspect, the present disclosure provides compounds having thestructure of Formula V:

or a pharmaceutically acceptable salt thereof,

-   -   wherein:    -   R₁ is H, —OH, —NH₂, or SH;    -   R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₃ is H, —OH, —NH₂, or SH;    -   R₆ and R₇ are each independently, at each occurrence, —OH, —NH₂,        —CN, —NO₂, —C(═O)OR^(b), —C(═O) N(R^(b))₂, —N(R^(b))C(═O)OR^(b),        halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, ═O, an optionally substituted        alkyl, an optionally substituted heteroalkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl or an optionally substituted alkoxy;    -   ring R is C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl,        or a 5- to 14-membered heteroaryl;

ring T is C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, or a 5-to 14-membered heteroaryl;

-   -   X is CH, S, or N;    -   Z is O or S;    -   L₁ is a bivalent radical selected from a bond, —C(═O)—,        —(C(═O)O)—, —OC(═O)—, —(C(═O)NR^(c))—, —N(R^(c))C(═O)—,        —N(R^(c))—, —S(═O)₂—, —(C₁₋₄ alkylene)-, —(C₁₋₄ alkylene)-O—,        —(C₁₋₄ alkylene)-N(R^(c))—, —(C₁₋₄ alkylene)-S—, or —(C₁₋₄        alkylene)-S(═O)₂—;    -   L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-(C(═O)NR₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-O—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-S(═O)₂—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-S(═O)₂N(R₅)—, or —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)S(═O)₂—;    -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl, on optionally substituted —(C₀₋₄        alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene), —(C₀₋₄        alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄        alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄        alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted heteroalkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl or an optionally substituted alkoxy;    -   L₃ is a bivalent radical selected from a bond, —(C₁₋₆        alkylene)-, —(C₂₋₆ alkenylene)-, or        —(C₂₋₆ alkynylene)-, —(C₃₋₁₀ heterocycloalkylene)-, —(C₆₋₁₄        arylene)-, -(5- to 14-membered heteroarylene)-;    -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl;    -   n is 1 or 2;    -   p is 0, 1, 2, or 3; and    -   r is 0, 1, 2, or 3.

In one embodiment, R₅ is —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄ alkylene)-(5- to 14-memberedheteroaryl).

In another embodiment, p is 1, and R₆ is ═O.

In yet another aspect, the present disclosure provides compounds havingthe structure of Formula VI:

or a pharmaceutically acceptable salt thereof,

-   -   wherein:    -   R₁ is H, C₁₋₆ alkyl, —OH, —NH₂, or SH;    -   R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₃ is H, C₁₋₆ alkyl, —OH, —NH₂, or SH;    -   R₆ and R₇ are each independently, at each occurrence, —OH, —NH₂,        —CN, —NO₂, —C(═O)OR^(b), —C(═O) N(R^(b))₂, —N(R^(b))C(═O)OR^(b),        halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, ═O, an optionally substituted        alkyl, an optionally substituted heteroalkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl or an optionally substituted alkoxy;    -   ring R is C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl,        or a 5- to 14-membered heteroaryl;    -   ring T is C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl,        or a 5- to 14-membered heteroaryl;    -   X is C(H), S, or N;    -   Z is O or S;    -   L₁ is a bivalent radical selected from a bond, —C(═O)—,        —(C(═O)O)—, —OC(═O)—, —(C(═O)NR^(b))—, —N(R^(b))C(═O)—,        —N(R^(b))—, —S(═O)₂—, —(C₁₋₄ alkylene)-, —(C₁₋₄ alkylene)-O—,        —(C₁₋₄ alkylene)-N(R^(b))—, —(C₁₋₄ alkylene)-S—, or —(C₁₋₄        alkylene)-S(═O)₂—;    -   L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-(C(═O)NR₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)C(═O)—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-O—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂N(R₅)—, or        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—S(═O)₂—,    -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl, on optionally substituted —(C₀₋₄        alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene), —(C₀₋₄        alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄        alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄        alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted heteroalkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl or an optionally substituted alkoxy;    -   L₃ is a bivalent radical selected from a bond, —(C₁₋₆        alkylene)-, —(C₂₋₆ alkenylene)-, or        —(C₂₋₆ alkynylene)-, —(C₃₋₁₀ heterocycloalkylene)-, —(C₆₋₁₄        arylene)-, -(5- to 14-membered heteroarylene)-;    -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl;    -   n is 1 or 2;    -   p is 0, 1, 2, or 3; and    -   r is 0, 1, 2, or 3.

In one embodiment, R₅ is —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄ alkylene)-(5- to 14-memberedheteroaryl).

In another embodiment, p is 1, and R₆ is ═O.

One embodiment provided herein describes a method of modulating theactivity of UDP-{3-O—[(R)-3-hydroxymyristoyl]}-N-acetylglucosaminedeacetylase in a subject in need thereof comprising administering atherapeutically effective amount of a compound described herein, or apharmaceutically acceptable salt thereof.

Also provided herein is a method of treating a gram-negative bacterialinfection in a subject comprising administering to the subject apharmaceutical composition comprising a compound described herein, or apharmaceutically acceptable salt thereof.

Another embodiment provided herein describes a pharmaceuticalcomposition comprising a therapeutically effective amount of a compounddescribed herein and a pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a synthetic scheme to prepare compounds 82, 83, 84 and 85.

FIG. 2 shows a synthetic scheme to prepare compound 91.

FIG. 3 shows a synthetic scheme to prepare compound 95.

FIG. 4 shows a synthetic scheme to prepare compound 70.

FIG. 5 shows a synthetic scheme to prepare compound 71.

FIG. 6 shows a synthetic scheme to prepare compound 72.

FIG. 7 shows a synthetic scheme to prepare compound 73.

FIG. 8 shows a synthetic scheme to prepare exemplary compounds of thedisclosure.

FIG. 9 shows a synthetic scheme to prepare compound 104.

FIG. 10 shows a synthetic scheme to prepare compound 105.

FIG. 11 shows a synthetic scheme to prepare compounds 107 and 108.

FIG. 12 shows a synthetic scheme to prepare compound 114.

FIG. 13 shows a dose response curve for compound Chir-90 in an LpxCinhibition assay.

FIG. 14 shows a dose response curve for compound 97 in an LpxCinhibition assay.

FIG. 15 shows a dose response curve for compound 98 in an LpxCinhibition assay.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, “treatment,” “treating,” “treat and the like refergenerally to obtaining a desired pharmacological or physiologicaleffect. The treatment may be therapeutic in terms of partial or completestabilization or cure of a disease or adverse effects caused by thedisease. “Treatment” as used herein covers any treatment of a disease ina subject, including: (a) inhibiting the symptoms of a disease, i.e.,arresting its development; or (b) relieving the symptoms of a disease,i.e., causing regression of the disease or symptoms.

The phrase “therapeutically effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present teachings that is effective for producing a desiredtherapeutic effect. Accordingly, a therapeutically effective amounttreats a disease or a disorder, e.g., ameliorates at least one sign orsymptom of the disorder. In various embodiments, the disease or disorderis a bacterial infection.

The term “alkyl” or “alkylene” as used herein refers to a fullysaturated straight or branched hydrocarbon. Preferably the alkylcomprises 1-22 carbon atoms, more preferably 1-16 carbon atoms, 1-8carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. Exemplary alkylgroups include, but are not limited to, methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl. Furthermore,the expression “C_(x)-C_(y)-alkyl”, wherein x is 1-5 and y is 2-10indicates a particular alkyl group (straight- or branched-chain) of aparticular range of carbons. For example, the expression C₁-C₄-alkylincludes, but is not limited to, methyl, ethyl, propyl, butyl,isopropyl, tert-butyl and isobutyl. Alkyl groups may be substituted withone or more substituents, each of which is independently selected from,e.g., (a) oxo (═O), fluoro (—F), chloro (—Cl), bromo (—Br), iodo (—I),cyano (—CN), and nitro (—NO₂); (b) substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, substituted or unsubstituted C₃₋₁₀cycloalkyl, substituted or unsubstituted C₆₋₁₄ aryl, substituted orunsubstituted C₇₋₁₅ aralkyl, substituted or unsubstituted heteroaryl,and substituted or unsubstituted heterocyclyl; and (c) —C(O)R^(a),—C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a),—OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c),—OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c),—NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), R^(d), and R^(e) are eachindependently, at each occurrence, H or C₁₋₆ alkyl.

The term “alkenyl” or “alkenylene,” alone or in combination refers to astraight-chain, cyclic or branched hydrocarbon residue comprising atleast one olefinic bond and the indicated number of carbon atoms.Preferred alkenyl groups have up to 8, preferably up to 6, particularlypreferred up to 4 carbon atoms. Examples of alkenyl groups include, butare not limited to, ethenyl, 1-propenyl, 2-propenyl, isopropenyl,1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-cyclopentenyl,1-cyclohexenyl, and 2,4-hexadiene. Alkenyl groups may be substitutedwith one or more substituents, each of which is independently selectedfrom, e.g., (a) oxo (═O), fluoro (—F), chloro (—Cl), bromo (—Br), iodo(—I), cyano (—CN), and nitro (—NO₂); (b) substituted or unsubstitutedC₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, substituted or unsubstituted C₃₋₁₀cycloalkyl, substituted or unsubstituted C₆₋₁₄ aryl, substituted orunsubstituted C₇₋₁₅ aralkyl, substituted or unsubstituted heteroaryl,and substituted or unsubstituted heterocyclyl; and (c) —C(O)R^(a),—C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a),—OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c),—OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c),—NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), R^(d), and R^(e) are eachindependently, at each occurrence, H or C₁₋₆ alkyl.

The term “alkynyl” or “alkynylene” alone or in combination refers to astraight-chain, cyclic or branched hydrocarbon residue comprising atleast one carbon-carbon triple bond and the indicated number of carbonatoms. The alkynyl may contain one, two, or three carbon-carbon triplebonds. Preferred alkynyl groups have up to 8, preferably up to 6,particularly preferred up to 4 carbon atoms. Examples of alkynyl groupsinclude, but are not limited to, ethyne (or acetylene), 1-propyne,2-propyne, 1-butyne, 2-butyne, 3-butyne, isobutyne, 1-cyclopentynyl,1-cyclohexynyl, and 2,4-hexadiyne. Alkynyl groups may be substitutedwith one or more substituents, each of which is independently selectedfrom, e.g., (a) oxo (═O), fluoro (—F), chloro (—Cl), bromo (—Br), iodo(—I), cyano (—CN), and nitro (—NO₂); (b) substituted or unsubstitutedC₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, substituted or unsubstituted C₃₋₁₀cycloalkyl, substituted or unsubstituted C₆₋₁₄ aryl, substituted orunsubstituted C₇₋₁₅ aralkyl, substituted or unsubstituted heteroaryl,and substituted or unsubstituted heterocyclyl; and (c) —C(O)R^(a),—C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a),—OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c),—OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c),—NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), R^(d), and R^(e) are eachindependently, at each occurrence, H or C₁₋₆ alkyl.

The term “alkoxy” represents a chemical substituent of formula —OR,where R is a C₁₋₂₀ alkyl group (e.g., C₁₋₆ or C₁₋₁₀ alkyl), unlessotherwise specified. An alkoxy group refers to those alkyl groups,having from 1 to 20 carbon atoms, attached to the remainder of themolecule via an oxygen atom. Exemplary alkoxy groups include methoxy,ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and thelike. In some embodiments, the alkyl group can be further substitutedwith 1, 2, 3, or 4 substituent groups as defined herein (e.g., hydroxyor alkoxy).

The term “cycloalkyl” or “carbocyclic” as used herein refers to asaturated or unsaturated monocyclic, bicyclic, tricyclic, othermulticyclic, or bridged cyclic hydrocarbon group. A cycloalkyl group canhave 3-22 ring carbon atoms, 3-12 ring carbon atoms, or 3-7 ring carbonatoms, referred to herein as C₃-C₂₂ cycloalkyl, C₃-C₁₂ cycloalkyl, orC₃-C₇ cycloalkyl, respectively. A cycloalkyl group can also have one ormore carbon-carbon double bond or carbon-carbon triple bond. Cycloalkylgroups may be substituted with one or more substituents, each of whichis independently selected from, e.g., (a) oxo (═O), fluoro (—F), chloro(—Cl), bromo (—Br), iodo (—I), cyano (—CN), and nitro (—NO₂); (b)substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₁₀ cycloalkyl, substituted or unsubstituted C₆₋₁₄ aryl,substituted or unsubstituted C₇₋₁₅ aralkyl, substituted or unsubstitutedheteroaryl, and substituted or unsubstituted heterocyclyl; and (c)—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), R^(d), and R^(e) are eachindependently, at each occurrence, H or C₁₋₆ alkyl.

Exemplary monocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like. Exemplary bicyclic hydrocarbon groups includebornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groupsinclude adamantyl and the like. Cycloalkyl groups can be fused to othercycloalkyl saturated or unsaturated, aryl, or heterocyclyl groups.

The term “aryl” or “arylene” as used herein refers to a mono-, bi-, orother multi-carbocyclic aromatic ring system. The aryl can have 6-14carbon atoms, or 6-10 carbon atoms, referred to herein as C₆-C₁₄ aryl,or C₆-C₁₀ aryl, respectively. The aryl group can optionally be fused toone or more rings selected from aryls and cycloalkyls. The ring systemsmay be partially saturated. The term “biaryl” as used herein refers toan aryl group fused or bridged to another aromatic or non-aromaticcarbocyclic. The aryl may be C₆₋₂₀ biaryl. Exemplary aryl groupsinclude, but are not limited to, phenyl, biphenyl, tolyl, anthracenyl,xylyl, anthryl, and naphthyl, as well as benzo-fused carbocyclicmoieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups alsoinclude, but are not limited to a monocyclic aromatic ring system,wherein the ring comprises 6 carbon atoms, referred to herein as “C₆aryl” or phenyl. The phenyl group can also be fused to a cyclohexane orcyclopentane ring to form a biaryl. Aryl groups may be substituted withone or more substituents, each of which is independently selected from,e.g., (a) oxo (═O), fluoro (—F), chloro (—Cl), bromo (—Br), iodo (—I),cyano (—CN), and nitro (—NO₂); (b) substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, substituted or unsubstituted C₃₋₁₀cycloalkyl, substituted or unsubstituted C₆₋₁₄ aryl, substituted orunsubstituted C₇₋₁₅ aralkyl, substituted or unsubstituted heteroaryl,and substituted or unsubstituted heterocyclyl; and (c) —C(O)R^(a),—C(O)OR^(d), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a),—OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c),—OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c),—NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(d)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), R^(d), and R^(e) are eachindependently, at each occurrence, H or C₁₋₆ alkyl.

The term “heterocycle” or “heterocyclyl” refers to a fully saturated orpartially unsaturated nonaromatic monocyclic, bicyclic, tricyclic, othermulticyclic, or bridged heterocyclic group containing at least oneheteroatom such as nitrogen, oxygen, or sulfur. In some cases, theheterocycle can be 3- to 22-membered rings, 4- to 13-membered ringstructures or 3- to 7-membered rings, whose ring structures include oneto four heteroatoms. The heterocycle may also be referred to as C₃₋₁₀heterocycloalkyl comprising 3 to 10 carbon atoms and 1 to 3 heteroatomsto form a 4- to 13-membered heterocycloalkyl. Nonlimiting examplesinclude piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl orpirazinyl. In some case, the heterocycle is a nitrogen heterocycle,wherein at least one ring comprises at least one nitrogen ring atom. Theheterocycles may be fused to other rings to form a polycyclicheterocycloalkyl. Thus, heterocycloalkyls also include bicyclic,tricyclic, and tetracyclic groups in which any of the above heterocyclicrings is fused to one or two rings independently selected fromcycloalkyls, and heterocycles. The heterocycle may also be fused to aspirocyclic group. Heterocycle groups may be substituted with one ormore substituents, each of which is independently selected from, e.g.,(a) oxo (═O), fluoro (—F), chloro (—Cl), bromo (—Br), iodo (—I), cyano(—CN), and nitro (—NO₂); (b) substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₁₀ cycloalkyl, substitutedor unsubstituted C₆₋₁₄ aryl, substituted or unsubstituted C₇₋₁₅ aralkyl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocyclyl; and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(d)S(O)₂NR^(b)R^(c), —P(O)R^(a)R^(d),—P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at eachoccurrence, H or C₁₋₆ alkyl.

Heterocycle groups within the scope of this definition include but arenot limited to imidazolyl, isothiazolyl, thiazolyl, triazinyl,triazolyl, pyrolidinyl, pyrrolinyl, piperidinyl, morpholinyl,piperazinyl, thiomorpholinyl, pyranyl and pyrazlonyl.

The term “heteroaromatic,” “heteroaryl,” or “heteroarylene” as usedherein refers to a mono-, bi-, tricyclic, or multi-cyclic aromatic ringsystem containing one or more heteroatoms, for example 1-4 heteroatoms,such as nitrogen, oxygen, and sulfur. For example, a bicyclic aromaticring system containing one or more heteroatoms includes, but is notlimited to, phenylpyridine, triazolylpyridine, oxazolylpyridine,thiazolylpyridine, and imidazolylpyridine. Heteroaryls can also be fusedto non-aromatic rings. In various embodiments, the term “heteroaromatic”or “heteroaryl,” as used herein except where noted, represents a stable5- to 7-membered monocyclic, stable 9- to 10-membered fused bicyclic, ora stable 12- to 14-membered fused tricyclic heterocyclic ring system, ora stable 5- to 14-membered heteroarylene, which contains an aromaticring that contains at least one heteroatom selected from the groupconsisting of nitrogen, oxygen, and sulfur. In some embodiments, atleast one nitrogen atom is in the aromatic ring. Heteroaryl groups maybe substituted with one or more substituents, each of which isindependently selected from, e.g., (a) oxo (═O), fluoro (—F), chloro(—Cl), bromo (—Br), iodo (—I), cyano (—CN), and nitro (—NO₂); (b)substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₁₀ cycloalkyl, substituted or unsubstituted C₆₋₁₄ aryl,substituted or unsubstituted C₇₋₁₅ aralkyl, substituted or unsubstitutedheteroaryl, and substituted or unsubstituted heterocyclyl; and (c)—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), R^(d), and R^(e) are eachindependently, at each occurrence, H or C₁₋₆ alkyl.

The terms “heterobiaryl” and “heterobicycloalkyl” as used herein refersto a heteroaryl group fused to another aromatic or non-aromaticcarbocyclic or heterocyclic ring. Exemplary heterobiaryls andheterobicycloalkyls include, but are not limited to 5,6- or 6,6-fusedsystems, wherein one or both rings contain heteroatoms. The termheterobiaryl or heterobicycloalkyl also encompasses reduced or partlyreduced forms of fused aromatic system wherein one or both rings containring heteroatoms. The ring system may contain up to four heteroatoms,independently selected from oxygen, nitrogen, and sulfur. These groupsmay also be referred to as “C₈₋₁₁ heterobiaryl,” “fused 5- to12-membered heterobicycloalkyl,” and fused 8- to 11-memberedheterobiaryl. Heterobiaryl groups may be substituted with one or moresubstituents, each of which is independently selected from, e.g., (a)oxo (═O), fluoro (—F), chloro (—Cl), bromo (—Br), iodo (—I), cyano(—CN), and nitro (—NO₂); (b) substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₁₀ cycloalkyl, substitutedor unsubstituted C₆₋₁₄ aryl, substituted or unsubstituted C₇₋₁₅ aralkyl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocyclyl; and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —P(O)R^(a)R^(d),—P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at eachoccurrence, H or C₁₋₆ alkyl.

Heteroaryl groups within the scope of this definition include but arenot limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl,pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl,benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl,pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,tetrahydroquinoline.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom.

The terms “hydroxy” and “hydroxyl” as used herein refers to —OH.

The term “nitro” as used herein refers to —NO₂.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those which are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

The term “optionally substituted” is intended to mean that a group orsubstituent, such as an alkyl, alkylene, heteroalkylene, alkenyl,alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkenyl, aryl,aralkyl, heteroaryl, heteroaryl-C₁₋₆ alkyl, and heterocyclyl group, maybe substituted with one or more substituents, each of which isindependently selected from, e.g., (a) oxo (═O), fluoro (—F), chloro(—Cl), bromo (—Br), iodo (—I), cyano (—CN), and nitro (—NO₂); (b)substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₁₀ cycloalkyl, substituted or unsubstituted C₆₋₁₄ aryl,substituted or unsubstituted C₇₋₁₅ aralkyl, substituted or unsubstitutedheteroaryl, and substituted or unsubstituted heterocyclyl; and (c)—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), R^(d), and R^(e) are eachindependently, at each occurrence, H or C₁₋₆ alkyl.

The term “metal” as used herein refers to metals in elemental form,metal atoms, and metal ions interchangeably. The term “metal” alsoencompasses metal radioisotopes.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

As used herein, the term “pharmaceutically acceptable salt” refers toderivatives of the disclosed compounds wherein the parent compound ismodified by converting an existing acid or base moiety to its salt form.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts of thepresent disclosure include the conventional non-toxic salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. The pharmaceutically acceptable salts of the present disclosurecan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418 and Journal of PharmaceuticalScience, 66, 2 (1977), each of which is incorporated herein by referencein its entirety.

Compounds of the Disclosure

The present disclosure provides hydroxypyridinone andhydroxypyrimidinone derivatives, pharmaceutical compositions thereof,and methods of using such compounds to treat or alleviate a disease orcondition. Provided herein are compounds and compositions thereof usefulto treat bacterial infections.

In one aspect, the disclosure provides a metal-binding compoundcomprising a hydroxypyridinone or a hydroxypyrimidinone derivative. Insome embodiments, the metal-binding compound has the followingstructural formula with the positional numbering below:

In another embodiment, a compound of the disclosure has the followingstructural formula:

or a pharmaceutically acceptable salt thereof,

wherein:

R₁ is H, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₃ is —OH, —NH₂, or SH;

X is CH, S, or N;

Z is O or S;

L₁ is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—,—OC(═O)—, —(C(═O)NR^(b))—, —N(R^(b))C(═O)—, —N(R^(b))—, —S(═O)₂—, —(C₁₋₄alkylene)-, —(C₁₋₄ alkylene)-O—, —(C₁₋₄ alkylene)-N(R^(b))—, —(C₁₋₄alkylene)-S—, or —(C₁₋₄ alkylene)-S(═O)₂—;

L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-(C(═O)NR₅)—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-O—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-S(═O)₂N(R₅)—, or —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-N(R₅)S(═O)₂—;

wherein each R₄ is H or C₁₋₆ alkyl; and

each R₅ is independently H, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₁₋₆ heteroalkyl, an optionally substituted C₁₋₆alkenyl, an optionally substituted C₁₋₆ alkynyl, an optionallysubstituted C₆₋₁₄ aryl, an optionally substituted 5- to 14-memberedheteroaryl, an optionally substituted C₃-C₈ cycloalkyl, on optionallysubstituted —(C₀₋₄ alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene),alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄ alkylene)-halo,—(C₀₋₄ alkylene)-NO₂, —(C₀₋₄ alkylene)-N(R^(f))₂, —(C₀₋₄alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄ alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl), —(C₀₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄ alkylene)-NR^(b)C(═O)R^(f);

wherein each R^(f) is independently H, an optionally substituted alkyl,an optionally substituted heteroalkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl or an optionallysubstituted alkoxy;

L₃ is a bivalent radical selected from a bond, —(C₁₋₆ alkylene)-, —(C₂₋₆alkenylene)-, —(C₂₋₆ alkynylene)-, —(C₃₋₁₀ heterocycloalkylene)-,—(C₆₋₁₄ arylene)-, or -(5- to 14-membered heteroarylene)-;

L₄ is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—,—OC(═O)—, —(C(═O)NR^(e))—, —N(R^(e))C(═O)—, —N(R^(e))—, —S(═O)₂—, or—(C₁₋₄ alkylene)-;

G₁ and G₂ are each independently, at each occurrence, a bivalent radicalselected from —(C₆₋₁₄ arylene)- or -(5- to 14-membered heteroarylene)-;

G₃ is H, CN, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄aryl, 5- to 14-membered heteroarylene, fused 5- to 12-memberedheterobicycloalkyl, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), (5- to 14-membered heteroarylene)-(C₁₋₄ heteroalkyl),(fused 5- to 12-membered heterobicycloalkyl)-(C₁₋₄ heteroalkyl), or(fused 8- to 11-membered heterobiaryl)-(C₁₋₄ heteroalkyl); and

R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at eachoccurrence, H or C₁₋₆ alkyl; and

n is 1 or 2.

In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—, substituted orunsubstituted C₀₋₃ alkylene-C(═O)—, substituted or unsubstituted C₀₋₃alkylene-C(═N—OH)—, substituted or unsubstituted C₀₋₃alkylene-(C(═O)NR₅)—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-O—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted or unsubstituted C₀₋₃alkylene-S(═O)₂N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃ alkylene-C(═O)—,substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstitutedC₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—,substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂N(R₅)—, or substituted orunsubstituted C₀₋₃ alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ issubstituted or unsubstituted C₁₋₃ alkylene, substituted or unsubstitutedC₀₋₃ alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃alkylene-C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—.In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-O—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-O—, or substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. Insome embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene orsubstituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—,substituted or unsubstituted C₀₋₃ alkylene-C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted or unsubstitutedC₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, orsubstituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))— orsubstituted or unsubstituted C₀₋₃ alkylene-C(═O)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—.

In some embodiments of Formula I, Z is O. In another embodiment ofFormula I, Z is S. In still another embodiment, X is N. In yet anotherembodiment, L₁ bivalent radical selected from a bond, —(C₁₋₄alkylene)-O—, —(C₁₋₄ alkylene)-N(R^(b))—, —(C₁₋₄ alkylene)-S—, or —(C₁₋₄alkylene)-S(═O)₂—; R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆alkoxy; and R^(b) is H or C₁₋₆ alkyl. In one embodiment, R₅ is nothydrogen. In another embodiment, R₅ is —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄ alkylene)-(5- to 14-memberedheteroaryl). In certain embodiments, R₅ is —(C₁₋₄ alkylene)-OR^(d),—(C₁₋₄ alkylene)-N(R^(d))₂, or —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)).

In yet another embodiment, L₃ is a bivalent radical selected from —(C₂₋₆alkenylene)-, —(C₂₋₆ alkynylene)-, —(C₃₋₁₀ heterocycloalkylene)-,—(C₆₋₁₄ arylene)-, or -(5- to 14-membered heteroarylene)-. In stillanother embodiment, L₃ is a bond.

In some embodiments, each R₄ is H. In other embodiments, R₄ is H oroptionally substituted alkyl. In certain embodiments, R₄ is optionallysubstituted C₁₋₆ alkyl. In some embodiments, each R₄ is H or haloC₁₋₆alkyl.

In another embodiment of Formula I, R₅ is H, C₁₋₆ alkyl, —(C₁₋₄alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-S(═O)₂—(R), —(C₁₋₄ alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl). In some embodiments, each R₅is H, optionally substituted C₁₋₆ alkyl, —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered heteroaryl),—(C₁₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f).In another embodiment, each R₅ is H, C₁₋₆ alkyl, —(C₁₋₄alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄ alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl). In some embodiments, each R₅is H, —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f). In someembodiments, each R₅ is H, substituted C₁₋₆ alkyl, —(C₁₋₄alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f). Incertain embodiments, each R₅ is H, substituted C₁₋₆ alkyl, or —(C₁₋₄alkylene)-OR^(d).

In some embodiments, R^(f) is H, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, or optionally substitutedheteroaryl. In some embodiments, R^(f) is H, alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl. In someembodiments, R^(f) is H, alkyl, heteroalkyl, cycloalkyl, orheterocyclyl.

In other embodiments of Formula I, the compound has the followingstructural formula:

or a pharmaceutically acceptable salt thereof,

wherein:

R₁ is H, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₃ is —OH, —NH₂, or SH;

Z is O or S;

L₁ is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—,—(C(═O)NR^(b))—, —N(R^(b))C(═O)—, —(C₁₋₄ alkylene)-O—, —(C₁₋₄alkylene)-N(R^(b))—, —(C₁₋₄ alkylene)-S—, or —(C₁₋₄ alkylene)-S(═O)₂—;

L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-(C(═O)NR₅)—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-O—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—,—(C(R₄)(R₅))_(n)(C₀₋₃ alkylene)-S(═O)₂—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-S(═O)₂N(R₅)—, or —(C(R₄)(R₅))_(n)(C₀₋₃ alkylene)-N(R₅)S(═O)₂—;

wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and

each R₅ is independently H, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₁₋₆ heteroalkyl, an optionally substituted C₁₋₆alkenyl, an optionally substituted C₁₋₆ alkynyl, an optionallysubstituted C₆₋₁₄ aryl, an optionally substituted 5- to 14-memberedheteroaryl, an optionally substituted C₃-C₈ cycloalkyl, on optionallysubstituted —(C₀₋₄ alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene),—(C₀₋₄ alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄ alkylene)-halo,—(C₀₋₄ alkylene)-NO₂, —(C₀₋₄ alkylene)-N(R^(f))₂, —(C₀₋₄alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄ alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl), —(C₀₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄ alkylene)-NR^(b)C(═O)R^(f);

wherein each R^(f) is independently H, an optionally substituted alkyl,an optionally substituted heteroalkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl or an optionallysubstituted alkoxy;

L₃ is a bivalent radical selected from —(C₂₋₆ alkenylene)- or —(C₂₋₆alkynylene)-;

L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,—(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;

G₁ and G₂ are each independently, at each occurrence, a bivalent radicalselected from —(C₆₋₁₄ arylene)- or -(5- to 14-membered heteroarylene)-;

G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), an optionally substituted alkyl, an optionally substitutedheteroalkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl or an optionally substituted alkoxy;

R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at eachoccurrence, H or C₁₋₆ alkyl; and

n is 1 or 2.

In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—, substituted orunsubstituted C₀₋₃ alkylene-C(═O)—, substituted or unsubstituted C₀₋₃alkylene-C(═N—OH)—, substituted or unsubstituted C₀₋₃alkylene-(C(═O)NR₅)—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-O—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted or unsubstituted C₀₋₃alkylene-S(═O)₂N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃ alkylene-C(═O)—,substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstitutedC₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—,substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂N(R₅)—, or substituted orunsubstituted C₀₋₃ alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ issubstituted or unsubstituted C₁₋₃ alkylene, substituted or unsubstitutedC₀₋₃ alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃alkylene-C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—.In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-O—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-O—, or substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. Insome embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene orsubstituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—,substituted or unsubstituted C₀₋₃ alkylene-C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted or unsubstitutedC₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, orsubstituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))— orsubstituted or unsubstituted C₀₋₃ alkylene-C(═O)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—.

In another embodiment of Formula II, L₃ is a bivalent radical —(C₁₋₆alkynylene)-. In some embodiments, L₃ comprises one or two carbon-carbontriple bonds. In another embodiment of Formula II,

R₁ is H or C₁₋₆ alkyl;

R₂ is H, —OR^(a), C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₃ is —OH;

Z is O;

L₁ is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—,—(C(═O)NR^(b))—, —N(R^(b))C(═O)—, —(C₁₋₄ alkylene)-N(R^(b))—, or —(C₁₋₄alkylene)-S(═O)₂—;

L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-(C(═O)NR₅)—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-O—, or —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—;

wherein each R₄ is H or C₁₋₆ alkyl; and

each R₅ is independently H, C₁₋₆ alkyl, —(C₁₋₄ alkylene)-OR^(f), —(C₁₋₄alkylene)-N(R^(f))₂, or —(C₁₋₄ alkylene)-S(═O)₂—(R^(f));

L₃ is a bivalent radical —(C₁₋₆ alkynylene)-;

L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,—(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;

G₁ and G₂ are each independently, at each occurrence, a bivalent radicalselected from —(C₆ arylene)- or -(5- to 6-membered heteroarylene)-;

G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), an optionally substituted alkyl, an optionally substitutedheteroalkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl or an optionally substituted alkoxy;

R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at eachoccurrence, H or C₁₋₆ alkyl; and

n is 1 or 2.

In yet another embodiment of Formula II, L₄ is a bivalent radicalselected from —C(═O)— or —(C₁₋₄ alkylene)-. In still another embodimentof Formula II,

R₁ is H or C₁₋₆ alkyl;

R₂ is H or C₁₋₆ alkyl;

R₃ is —OH;

Z is O;

L₁ is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—,—(C(═O)NR^(b))—, or —N(R^(b))C(═O)—;

L₂ is a bivalent radical —(C(R₄)(R₅))_(n)(C₀₋₃ alkylene)-;

wherein each R₄ is H or C₁₋₆ alkyl; and

each R₅ is independently H, or C₁₋₆ alkyl;

L₃ is a bivalent radical —(C₁₋₆ alkynylene)-;

L₄ is a bivalent radical selected from —C(═O)— or —(C₁₋₄ alkylene)-;

G₁ and G₂ are each independently, at each occurrence, a bivalent radicalselected from —(C₆ arylene)- or -(5- to 6-membered heteroarylene)-;

G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), an optionally substituted alkyl, an optionally substitutedheteroalkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl or an optionally substituted alkoxy;

R^(b) is H or C₁₋₆ alkyl; and

n is 1.

In some embodiments, each R₄ is H. In other embodiments, R₄ is H oroptionally substituted alkyl. In certain embodiments, R₄ is optionallysubstituted C₁₋₆ alkyl. In some embodiments, each R₄ is H or haloC₁₋₆alkyl.

In another embodiment of Formula II, R₅ is H, C₁₋₆ alkyl, —(C₁₋₄alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄ alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl). In some embodiments, each R₅is H, optionally substituted C₁₋₆ alkyl, —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered heteroaryl),—(C₁₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f).In another embodiment, each R₅ is H, C₁₋₆ alkyl, —(C₁₋₄alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄ alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl). In some embodiments, each R₅is H, —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f). In someembodiments, each R₅ is H, substituted C₁₋₆ alkyl, —(C₁₋₄alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f). Incertain embodiments, each R₅ is H, substituted C₁₋₆ alkyl, or —(C₁₋₄alkylene)-OR^(d).

In some embodiments, R^(f) is H, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, or optionally substitutedheteroaryl. In some embodiments, R^(f) is H, alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl. In someembodiments, R^(f) is H, alkyl, heteroalkyl, cycloalkyl, orheterocyclyl.

In another aspect, a backbone of a compound is not attached to a ringnitrogen atom. In some embodiments, a compound of the disclosure has thefollowing structural formula:

or a pharmaceutically acceptable salt thereof,

wherein:

R₁ is H or C₁₋₆ alkyl;

R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₃ is H, C₁₋₆ alkyl, —OH, —NH₂, or SH;

X is CH, S, or N;

Z is O;

L₁ is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—,—OC(═O)—, —(C(═O)NR^(b))—, —N(R^(b))C(═O)—, —N(R^(b))—, —S(═O)₂—, —(C₁₋₄alkylene)-, —(C₁₋₄ alkylene)-O—, —(C₁₋₄ alkylene)-N(R^(b))—, —(C₁₋₄alkylene-S—, or —(C₁₋₄ alkylene)-S(═O)₂—;

L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-(C(═O)NR₅)—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-O—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-S(═O)₂N(R₅)—, or —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-N(R₅)S(═O)₂—;

wherein each R₄ is H or C₁₋₆ alkyl; and

each R₅ is independently H, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₁₋₆ heteroalkyl, an optionally substituted C₁₋₆alkenyl, an optionally substituted C₁₋₆ alkynyl, an optionallysubstituted C₆₋₁₄ aryl, an optionally substituted 5- to 14-memberedheteroaryl, an optionally substituted C₃-C₈ cycloalkyl, on optionallysubstituted —(C₀₋₄ alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene),—(C₀₋₄ alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄ alkylene)-halo,—(C₀₋₄ alkylene)-NO₂, —(C₀₋₄ alkylene)-N(R^(f))₂, —(C₀₋₄alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄ alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl), —(C₀₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄ alkylene)-NR^(b)C(═O)R^(f);

wherein each R^(f) is independently H, an optionally substituted alkyl,an optionally substituted heteroalkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl or an optionallysubstituted alkoxy;

L₃ is a bivalent radical selected from a bond, —(C₁₋₆ alkylene)-, —(C₂₋₆alkenylene)-, —(C₂₋₆ alkynylene)-, —(C₃₋₁₀ heterocycloalkylene)-,—(C₆₋₁₄ arylene)-, or -(5- to 14-membered heteroarylene)-;

L₄ is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—,—OC(═O)—, —(C(═O)NR^(e))—, —N(R^(e))C(═O)—, —N(R^(e))—, —S(═O)₂—, or—(C₁₋₄ alkylene)-;

G₁ and G₂ are each independently, at each occurrence, a bivalent radicalselected from —(C₆₋₁₄ arylene)- or -(5- to 14-membered heteroarylene)-;

G₃ is H, CN, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄aryl, 5- to 14-membered heteroarylene, fused 5- to 12-memberedheterobicycloalkyl, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), (5- to 14-membered heteroarylene)-(C₁₋₄ heteroalkyl),(fused 5- to 12-membered heterobicycloalkyl)-(C₁₋₄ heteroalkyl), or(fused 8- to 11-membered heterobiaryl)-(C₁₋₄ heteroalkyl); and

R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at eachoccurrence, H or C₁₋₆ alkyl; and

n is 1 or 2,

provided that R₁ or R₃ is —OH, —NH₂, or SH.

In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—, substituted orunsubstituted C₀₋₃ alkylene-C(═O)—, substituted or unsubstituted C₀₋₃alkylene-C(═N—OH)—, substituted or unsubstituted C₀₋₃alkylene-(C(═O)NR₅)—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-O—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted or unsubstituted C₀₋₃alkylene-S(═O)₂N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃ alkylene-C(═O)—,substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstitutedC₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—,substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂N(R₅)—, or substituted orunsubstituted C₀₋₃ alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ issubstituted or unsubstituted C₁₋₃ alkylene, substituted or unsubstitutedC₀₋₃ alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃alkylene-C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—.In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-O—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-O—, or substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. Insome embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene orsubstituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—,substituted or unsubstituted C₀₋₃ alkylene-C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted or unsubstitutedC₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, orsubstituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))— orsubstituted or unsubstituted C₀₋₃ alkylene-C(═O)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—.

In some embodiments of Formula III, Z is O. In another embodiment ofFormula III, Z is S. In still another embodiment, X is N. In yet anotherembodiment, L₁ bivalent radical selected from a bond, —(C₁₋₄alkylene)-O—, —(C₁₋₄ alkylene)-N(R^(b))—, —(C₁₋₄ alkylene)-S—, or —(C₁₋₄alkylene)-S(═O)₂—; R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆alkoxy; and R^(b) is H or C₁₋₆ alkyl. In one embodiment, R₅ is nothydrogen. In another embodiment, R₅ is —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄ alkylene)-(5- to 14-memberedheteroaryl). In certain embodiments, R₅ is —(C₁₋₄ alkylene)-OR^(d),—(C₁₋₄ alkylene)-N(R^(d))₂, or —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)). In yetanother embodiment, L₃ is a bivalent radical selected from —(C₂₋₆alkenylene)-, —(C₂₋₆ alkynylene)-, —(C₃₋₁₀ heterocycloalkylene)-,—(C₆₋₁₄ arylene)-, or -(5- to 14-membered heteroarylene)-. In stillanother embodiment, L₃ is a bond.

In some embodiments, each R₄ is H. In other embodiments, R₄ is H oroptionally substituted alkyl. In certain embodiments, R₄ is optionallysubstituted C₁₋₆ alkyl. In some embodiments, each R₄ is H or haloC₁₋₆alkyl.

In another embodiment of Formula III, R₅ is H, C₁₋₆ alkyl, —(C₁₋₄alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄ alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl). In some embodiments, each R₅is H, optionally substituted C₁₋₆ alkyl, —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered heteroaryl),—(C₁₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f).In another embodiment, each R₅ is H, C₁₋₆ alkyl, —(C₁₋₄alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄ alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl). In some embodiments, each R₅is H, —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f). In someembodiments, each R₅ is H, substituted C₁₋₆ alkyl, —(C₁₋₄alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f). Incertain embodiments, each R₅ is H, substituted C₁₋₆ alkyl, or —(C₁₋₄alkylene)-OR^(d).

In some embodiments, R^(f) is H, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, or optionally substitutedheteroaryl. In some embodiments, R^(f) is H, alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl. In someembodiments, R^(f) is H, alkyl, heteroalkyl, cycloalkyl, orheterocyclyl.

In other embodiments of Formula III, the compound has the followingstructural formula:

or a pharmaceutically acceptable salt thereof,

wherein:

R₁ is H or C₁₋₆ alkyl;

R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

L₁ a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—,—OC(═O)—, —(C(═O)NR^(b))—, —N(R^(b))C(═O)—, —N(R^(b))—, —S(═O)₂—, —(C₁₋₄alkylene)-, —(C₁₋₄ alkylene)-O—, —(C₁₋₄ alkylene)-N(R^(b))—, —(C₁₋₄alkylene)-S—, or —(C₁₋₄ alkylene)-S(═O)₂—;

L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-(C(═O)NR₅)—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-O—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—,—(C(R₄)(R₅))_(n)(C₀₋₃ alkylene)-S(═O)₂—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-S(═O)₂N(R₅)—, or —(C(R₄)(R₅))_(n)(C₀₋₃ alkylene)-N(R₅)S(═O)₂—;

wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and

each R₅ is independently H, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₁₋₆ heteroalkyl, an optionally substituted C₁₋₆alkenyl, an optionally substituted C₁₋₆ alkynyl, an optionallysubstituted C₆₋₁₄ aryl, an optionally substituted 5- to 14-memberedheteroaryl, an optionally substituted C₃-C₈ cycloalkyl, on optionallysubstituted —(C₀₋₄ alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene),—(C₀₋₄ alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄ alkylene)-halo,—(C₀₋₄ alkylene)-NO₂, —(C₀₋₄ alkylene)-N(R^(f))₂, —(C₀₋₄alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄ alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl), —(C₀₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄ alkylene)-NR^(b)C(═O)R^(f);

wherein R^(f) is H, an optionally substituted alkyl, an optionallysubstituted heteroalkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl or an optionally substituted alkoxy;

L₃ is a bivalent radical selected from —(C₂₋₆ alkenylene)- or —(C₂₋₆alkynylene)-;

L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,—(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;

G₁ and G₂ are each independently, at each occurrence, a bivalent radicalselected from —(C₆₋₁₄ arylene)- or -(5- to 14-membered heteroarylene)-;

G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), an optionally substituted alkyl, an optionally substitutedheteroalkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl or an optionally substituted alkoxy; and

R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at eachoccurrence, H or C₁₋₆ alkyl; and

n is 1 or 2.

In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—, substituted orunsubstituted C₀₋₃ alkylene-C(═O)—, substituted or unsubstituted C₀₋₃alkylene-C(═N—OH)—, substituted or unsubstituted C₀₋₃alkylene-(C(═O)NR₅)—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-O—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted or unsubstituted C₀₋₃alkylene-S(═O)₂N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃ alkylene-C(═O)—,substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstitutedC₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—,substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂N(R₅)—, or substituted orunsubstituted C₀₋₃ alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ issubstituted or unsubstituted C₁₋₃ alkylene, substituted or unsubstitutedC₀₋₃ alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃alkylene-C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—.In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-O—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-O—, or substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. Insome embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene orsubstituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—,substituted or unsubstituted C₀₋₃ alkylene-C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted or unsubstitutedC₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, orsubstituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))— orsubstituted or unsubstituted C₀₋₃ alkylene-C(═O)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—.

In some embodiments of Formula IV,

R₁ is H or C₁₋₆ alkyl;

R₂ is H or C₁₋₆ alkyl;

L₁ is a bivalent radical selected from a bond, —(C(═O)O)—,—(C(═O)NR^(b))—, —N(R^(b))C(═O)—, a bond, —(C₁₋₄ alkylene)-O—, —(C₁₋₄alkylene)-N(R^(b))—, or —(C₁₋₄ alkylene)-S(═O)₂—;

L₂ is a bivalent radical is selected from —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene) or —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—;

wherein each R₄ is H or C₁₋₆ alkyl; and

each R₅ is independently H or C₁₋₆ alkyl, —C(═O)NR^(b)R^(f) or —(C₁₋₄alkylene)-NR^(b)C(═O)R^(f);

wherein each R^(f) is independently H, an optionally substituted alkyl,an optionally substituted heteroalkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl or an optionallysubstituted alkoxy;

L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,—(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;

G₁ and G₂ are each independently, at each occurrence, a bivalent radicalselected from —(C₆₋₁₄ arylene)- or -(5- to 14-membered heteroarylene)-;

G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), an optionally substituted alkyl, an optionally substitutedheteroalkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl or an optionally substituted alkoxy; and

R^(b) and R^(e) are each independently, at each occurrence, H or C₁₋₆alkyl; and

n is 1 or 2.

In some embodiments, L₁ is a bond, —(C₁₋₄ alkylene)-O—, —(C₁₋₄alkylene)-N(R^(b))—, —(C₁₋₄ alkylene)-S—, or —(C₁₋₄ alkylene)-S(═O)₂—;R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy; and R^(b) is Hor C₁₋₆ alkyl. In some embodiments, L₁ is a bond, —(C₁₋₄ alkylene)-O—,—(C₁₋₄ alkylene)-N(R^(b))—; R₂ is H, C₁₋₆ alkyl, or C₁₋₆ alkoxy; andR^(b) is H or C₁₋₆ alkyl. In some embodiments, L₁ is a bond; R₂ is H,C₁₋₆ alkyl. In some embodiments, L₁ is a bond; R₂ is H.

In some embodiments, L₂ is —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-,—(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-O—, or —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—. In certainembodiments, L₂ is —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-O—, or —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-N(R₅)—. In some embodiments, L₂ is —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)- or —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—.

In some embodiments, each R₄ is H. In other embodiments, R₄ is H oroptionally substituted alkyl. In certain embodiments, R₄ is optionallysubstituted C₁₋₆ alkyl. In some embodiments, each R₄ is H or haloC₁₋₆alkyl.

In some embodiments, each R₅ is H, optionally substituted C₁₋₆ alkyl,—(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄ alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl), —(C₁₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f). Inanother embodiment, each R₅ is H, C₁₋₆ alkyl, —(C₁₋₄ alkylene)-OR^(d),—(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄ alkylene)-(5- to 14-memberedheteroaryl). In some embodiments, each R₅ is H, —(C₁₋₄ alkylene)-OR^(d),—(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄alkylene)-NR^(b)C(═O)R^(f). In some embodiments, each R₅ is H,substituted C₁₋₆ alkyl, —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄alkylene)-NR^(b)C(═O)R^(f). In certain embodiments, each R₅ is H,substituted C₁₋₆ alkyl, or —(C₁₋₄ alkylene)-OR^(d).

In some embodiments, R^(f) is H, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, or optionally substitutedheteroaryl. In some embodiments, R^(f) is H, alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl. In someembodiments, R^(f) is H, alkyl, heteroalkyl, cycloalkyl, orheterocyclyl.

In some embodiments, each R₅ is —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered heteroaryl),—C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f); wherein R^(f) isH, an optionally substituted alkyl, an optionally substitutedheteroalkyl, an optionally substituted cycloalkyl or an optionallysubstituted heterocyclyl.

In some embodiments, L₄ is —C(═O)—. In some embodiments, L₄ is—(C(═O)O)—. In some embodiments, L₄ is —(C(═O)NR^(e))—. In someembodiments, L₄ is —N(R^(e))C(═O)— In some embodiments, L₄ is —(C₁₋₄alkylene)-.

In some embodiments, G₁ and G₂ are —(C₆₋₁₄ arylene)-. In otherembodiments, G₁ and G₂ are -(5- to 14-membered heteroarylene)-.

In some embodiments, G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl,C₆₋₁₄ aryl, 5- to 14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄heteroalkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ heteroalkyl), an optionally substitutedalkyl, an optionally substituted heteroalkyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedheterocyclyl, or an optionally substituted alkoxy. In some embodiments,G₃ is C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), an optionally substituted alkyl, or an optionallysubstituted heteroalkyl. In some embodiments, G₃ is C₃₋₇ cycloalkyl,C₃₋₁₀ heterocycloalkyl, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), or (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl). In some embodiments, G₃ is C₃₋₇ cycloalkyl. In someembodiments, G₃ is C₃₋₁₀ heterocycloalkyl. In some embodiments, G₃ is(C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl). In some embodiments, G₃ is (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl). In some embodiments, G₃ is (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ heteroalkyl).

In another embodiment, a compound of the disclosure has the followingstructural formula:

or a pharmaceutically acceptable salt thereof, wherein;

-   -   L₂ is —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃        alkylene)-(C—OR^(c))—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-O—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)—, or —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂—;

wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and

each R₅ is independently H, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₁₋₆ heteroalkyl, an optionally substituted C₁₋₆alkenyl, an optionally substituted C₁₋₆ alkynyl, an optionallysubstituted C₆₋₁₄ aryl, an optionally substituted 5- to 14-memberedheteroaryl, an optionally substituted C₃-C₈ cycloalkyl, on optionallysubstituted —(C₀₋₄ alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene),—(C₀₋₄ alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄ alkylene)-halo,—(C₀₋₄ alkylene)-NO₂, —(C₀₋₄ alkylene)-N(R^(f))₂, —(C₀₋₄alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄ alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl), —(C₀₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄ alkylene)-NR^(b)C(═O)R^(f);

wherein each R^(f) is independently H, an optionally substituted alkyl,an optionally substituted cycloalkyl, an optionally substitutedheterocyclyl, or an optionally substituted alkoxy;

L₃ is —(C₂₋₆ alkynylene)-;

L₄ is —C(═O)—, —(C(═O)O)—, —(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄alkylene)-;

G₁ and G₂ are each independently, at each occurrence, —(C₆₋₁₄ arylene)-;

G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), an optionally substituted alkyl, an optionally substitutedheteroalkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, or an optionally substituted alkoxy; and

R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at eachoccurrence, H or C₁₋₆ alkyl; and

n is 1 or 2.

In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—, substituted orunsubstituted C₀₋₃ alkylene-C(═O)—, substituted or unsubstituted C₀₋₃alkylene-C(═N—OH)—, substituted or unsubstituted C₀₋₃alkylene-(C(═O)NR₅)—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-O—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted or unsubstituted C₀₋₃alkylene-S(═O)₂N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃ alkylene-C(═O)—,substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstitutedC₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—,substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂N(R₅)—, or substituted orunsubstituted C₀₋₃ alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ issubstituted or unsubstituted C₁₋₃ alkylene, substituted or unsubstitutedC₀₋₃ alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃alkylene-C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—.In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-O—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-O—, or substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. Insome embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene orsubstituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—,substituted or unsubstituted C₀₋₃ alkylene-C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted or unsubstitutedC₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, orsubstituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))— orsubstituted or unsubstituted C₀₋₃ alkylene-C(═O)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—.

Some embodiments provided herein describe a compound of Formula IVA,wherein

-   -   L₂ is —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂—;    -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl, on optionally substituted —(C₀₋₄        alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene), —(C₀₋₄        alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄        alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄        alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted cycloalkyl, an optionally        substituted heterocyclyl, or an optionally substituted alkoxy;    -   L₃ is —(C₂₋₆ alkynylene)-;    -   L₄ is —C(═O)—, —(C(═O)O)—, —(C(═O)NR^(e))—, or —(C₁₋₄        alkylene)-;    -   G₁ and G₂ are each independently, at each occurrence, —(C₆₋₁₄        arylene)-;    -   G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5-        to 14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄        heteroalkyl), (C₁₋₄ alkylene)-(C₁₋₄ heterocycloalkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀        heterocycloalkylene)-(C₃₋₁₀ heterocycloalkyl), C₁₋₆ alkyl, or        (C₃₋₁₀ heterocycloalkylene)-hydroxy; and    -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl; and    -   n is 1 or 2.

In some embodiments, L₂ is —(C(R₄)(R₅))_(n)(C₀₋₃ alkylene)-,—(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—, —(C(R₄)(R₅))_(n)(C₀₋₃alkylene)-O—, or —(C(R₄)(R₅))_(n)(C₀₋₃ alkylene)-N(R₅)—. In certainembodiments, L₂ is —(C(R₄)(R₅))_(n)(C₀₋₃ alkylene)-,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-O—, or —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-N(R₅)—. In some embodiments, L₂ is —(C(R₄)(R₅))_(n)(C₀₋₃alkylene)- or —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—.

In some embodiments, each R₄ is H. In other embodiments, R₄ is H oroptionally substituted alkyl. In certain embodiments, R₄ is optionallysubstituted C₁₋₆ alkyl. In some embodiments, each R₄ is H or haloC₁₋₆alkyl.

In some embodiments, each R₅ is H, optionally substituted C₁₋₆ alkyl,—(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄ alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl), —(C₁₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f). Inanother embodiment, each R₅ is H, C₁₋₆ alkyl, —(C₁₋₄ alkylene)-OR^(d),—(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄ alkylene)-(5- to 14-memberedheteroaryl). In some embodiments, each R₅ is H, —(C₁₋₄ alkylene)-OR^(d),—(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄alkylene)-NR^(b)C(═O)R^(f). In some embodiments, each R₅ is H,substituted C₁₋₆ alkyl, —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄alkylene)-NR^(b)C(═O)R^(f). In certain embodiments, each R₅ is H,substituted C₁₋₆ alkyl, or —(C₁₋₄ alkylene)-OR^(d).

In some embodiments, R^(f) is H, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, or optionally substitutedheteroaryl. In some embodiments, R^(f) is H, alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl. In someembodiments, R^(f) is H, alkyl, heteroalkyl, cycloalkyl, orheterocyclyl.

In some embodiments, each R₅ is —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered heteroaryl),—C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f); wherein R^(f) isH, an optionally substituted alkyl, an optionally substitutedheteroalkyl, an optionally substituted cycloalkyl or an optionallysubstituted heterocyclyl.

In some embodiments, L₄ is —C(═O)—. In some embodiments, L₄ is—(C(═O)O)—. In some embodiments, L₄ is —(C(═O)NR^(e))—. In someembodiments, L₄ is —N(R^(e))C(═O)— In some embodiments, L₄ is —(C₁₋₄alkylene)-.

In some embodiments, G₁ and G₂ are —(C₆₋₁₄ arylene)-. In otherembodiments, G₁ and G₂ are -(5- to 14-membered heteroarylene)-.

In some embodiments, G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl,C₆₋₁₄ aryl, 5- to 14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄heteroalkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ heteroalkyl), an optionally substitutedalkyl, an optionally substituted heteroalkyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedheterocyclyl, or an optionally substituted alkoxy. In some embodiments,G₃ is C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), an optionally substituted alkyl, or an optionallysubstituted heteroalkyl. In some embodiments, G₃ is C₃₋₇ cycloalkyl,C₃₋₁₀ heterocycloalkyl, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), or (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl). In some embodiments, G₃ is C₃₋₇ cycloalkyl. In someembodiments, G₃ is C₃₋₁₀ heterocycloalkyl. In some embodiments, G₃ is(C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl). In some embodiments, G₃ is (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl). In some embodiments, G₃ is (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ heteroalkyl).

In some embodiments, G₃ is H, C₃₋₁₀ heterocycloalkyl, (C₁₋₄alkylene)-(C₁₋₄ heteroalkyl), (C₁₋₄ alkylene)-(C₁₋₄ heterocycloalkyl),(C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₃₋₁₀ heterocycloalkyl), C₁₋₆ alkyl, (C₃₋₁₀heterocycloalkylene)-hydroxy, or tetrazolyl.

In another embodiment, a compound of the disclosure has the followingstructural formula:

or a pharmaceutically acceptable salt thereof, wherein;

-   -   L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-O—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂—;    -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl, on optionally substituted —(C₀₋₄        alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene), —(C₀₋₄        alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄        alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄        alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted cycloalkyl, an optionally        substituted heterocyclyl, or an optionally substituted alkoxy;    -   L₃ is —(C₂₋₆ alkynylene)-;    -   L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,        —(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;    -   G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5-        to 14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄        heteroalkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ heteroalkyl), an optionally        substituted alkyl, an optionally substituted heteroalkyl, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted heterocyclyl, or an optionally substituted alkoxy;        and    -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl; and    -   n is 1 or 2.

Some embodiments provided herein describe a compound of Formula IVB, L₂is —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-N(R₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂—;

-   -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl, on optionally substituted —(C₀₋₄        alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene), —(C₀₋₄        alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄        alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄        alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted cycloalkyl, an optionally        substituted heterocyclyl, or an optionally substituted alkoxy;    -   L₃ is —(C₂₋₄ alkynylene)-;    -   L₄ is —C(═O)—, —(C(═O)O)—, —(C(═O)NR^(e))—, or —(C₁₋₄        alkylene)-;    -   G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5-        to 14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄        heteroalkyl), (C₁₋₄ alkylene)-(C₁₋₄ heterocycloalkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀        heterocycloalkylene)-(C₃₋₁₀ heterocycloalkyl), C₁₋₆ alkyl, or        (C₃₋₁₀ heterocycloalkylene)-hydroxy; and    -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl; and    -   n is 1 or 2.

In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—, substituted orunsubstituted C₀₋₃ alkylene-C(═O)—, substituted or unsubstituted C₀₋₃alkylene-C(═N—OH)—, substituted or unsubstituted C₀₋₃alkylene-(C(═O)NR₅)—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-O—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted or unsubstituted C₀₋₃alkylene-S(═O)₂N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃ alkylene-C(═O)—,substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstitutedC₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—,substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂N(R₅)—, or substituted orunsubstituted C₀₋₃ alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ issubstituted or unsubstituted C₁₋₃ alkylene, substituted or unsubstitutedC₀₋₃ alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃alkylene-C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—.In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-O—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-O—, or substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. Insome embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene orsubstituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—,substituted or unsubstituted C₀₋₃ alkylene-C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted or unsubstitutedC₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, orsubstituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))— orsubstituted or unsubstituted C₀₋₃ alkylene-C(═O)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—.

In some embodiments, L₂ is —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-,—(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-O—, or —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—. In certainembodiments, L₂ is —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-O—, or —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-N(R₅)—. In some embodiments, L₂ is —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)- or —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—.

In some embodiments, each R₄ is H. In other embodiments, R₄ is H oroptionally substituted alkyl. In certain embodiments, R₄ is optionallysubstituted C₁₋₆ alkyl. In some embodiments, each R₄ is H or haloC₁₋₆alkyl.

In some embodiments, each R₅ is H, optionally substituted C₁₋₆ alkyl,—(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄ alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl), —(C₁₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f). Inanother embodiment, each R₅ is H, C₁₋₆ alkyl, —(C₁₋₄ alkylene)-OR^(d),—(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄ alkylene)-(5- to 14-memberedheteroaryl). In some embodiments, each R₅ is H, —(C₁₋₄ alkylene)-OR^(d),—(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄alkylene)-NR^(b)C(═O)R^(f). In some embodiments, each R₅ is H,substituted C₁₋₆ alkyl, —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₁₋₄alkylene)-NR^(b)C(═O)R^(f). In certain embodiments, each R₅ is H,substituted C₁₋₆ alkyl, or —(C₁₋₄ alkylene)-OR^(d).

In some embodiments, R^(f) is H, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, or optionally substitutedheteroaryl. In some embodiments, R^(f) is H, alkyl, heteroalkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl. In someembodiments, R^(f) is H, alkyl, heteroalkyl, cycloalkyl, orheterocyclyl.

In some embodiments, each R₅ is —(C₁₋₄ alkylene)-OR^(d), —(C₁₋₄alkylene)-N(R^(d))₂, —(C₁₋₄ alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered heteroaryl),—C(═O)NR^(b)R^(f) or —(C₁₋₄ alkylene)-NR^(b)C(═O)R^(f); wherein R^(f) isH, an optionally substituted alkyl, an optionally substitutedheteroalkyl, an optionally substituted cycloalkyl or an optionallysubstituted heterocyclyl.

In some embodiments, L₃ is —(C₂-alkynylene)-. In other embodiments, L₃is —(C₄-alkynylene)-.

In some embodiments, L₄ is —C(═O)—. In some embodiments, L₄ is—(C(═O)O)—. In some embodiments, L₄ is —(C(═O)NR^(e))—. In someembodiments, L₄ is —N(R^(e))C(═O)— In some embodiments, L₄ is —(C₁₋₄alkylene)-.

In some embodiments, G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl,C₆₋₁₄ aryl, 5- to 14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄heteroalkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ heteroalkyl), an optionally substitutedalkyl, an optionally substituted heteroalkyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedheterocyclyl, or an optionally substituted alkoxy. In some embodiments,G₃ is C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), an optionally substituted alkyl, or an optionallysubstituted heteroalkyl. In some embodiments, G₃ is C₃₋₇ cycloalkyl,C₃₋₁₀ heterocycloalkyl, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), or (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl). In some embodiments, G₃ is C₃₋₇ cycloalkyl. In someembodiments, G₃ is C₃₋₁₀ heterocycloalkyl. In some embodiments, G₃ is(C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl). In some embodiments, G₃ is (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl). In some embodiments, G₃ is (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ heteroalkyl).

In some embodiments, G₃ is H, C₃₋₁₀ heterocycloalkyl, (C₁₋₄alkylene)-(C₁₋₄ heteroalkyl), (C₁₋₄ alkylene)-(C₁₋₄ heterocycloalkyl),(C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₃₋₁₀ heterocycloalkyl), C₁₋₆ alkyl, (C₃₋₁₀heterocycloalkylene)-hydroxy, or tetrazolyl.

In some embodiments, n is 1. In other embodiments, n is 2.

In still another aspect, the disclosure provides a compound of FormulaV:

or a pharmaceutically acceptable salt thereof,

wherein:

R₁ is H, —OH, —NH₂, or SH;

R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₃ is H, —OH, —NH₂, or SH;

R₆ and R₇ are each independently, at each occurrence, —OH, —NH₂, —CN,—NO₂, —C(═O)OR^(b), —C(═O) N(R^(b))₂, —N(R^(b))C(═O)OR^(b), halo, C₁₋₆alkyl, C₁₋₆ alkoxy, ═O, an optionally substituted alkyl, an optionallysubstituted heteroalkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl or an optionally substituted alkoxy;

ring R is C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, or a 5-to 14-membered heteroaryl;

ring T is C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, or a 5-to 14-membered heteroaryl;

X is CH, S, or N;

Z is O or S;

L₁ is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—,—OC(═O)—, —(C(═O)NR^(c))—, —N(R^(c))C(═O)—, —N(R^(c))—, —S(═O)₂—, —(C₁₋₄alkylene)-, —(C₁₋₄ alkylene)-O—, —(C₁₋₄ alkylene)-N(R^(c))—, —(C₁₋₄alkylene)-S—, or —(C₁₋₄ alkylene)-S(═O)₂—;

L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-(C(═O)NR₅)—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-O—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-S(═O)₂N(R₅)—, or —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-N(R₅)S(═O)₂—;

wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and

each R₅ is independently H, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₁₋₆ heteroalkyl, an optionally substituted C₁₋₆alkenyl, an optionally substituted C₁₋₆ alkynyl, an optionallysubstituted C₆₋₁₄ aryl, an optionally substituted 5- to 14-memberedheteroaryl, an optionally substituted C₃-C₈ cycloalkyl, on optionallysubstituted —(C₀₋₄ alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene),—(C₀₋₄ alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄ alkylene)-halo,—(C₀₋₄ alkylene)-NO₂, —(C₀₋₄ alkylene)-N(R^(f))₂, —(C₀₋₄alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄ alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl), —(C₀₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄ alkylene)-NR^(b)C(═O)R^(f);

wherein each R^(f) is independently H, an optionally substituted alkyl,an optionally substituted heteroalkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl or an optionallysubstituted alkoxy;

L₃ is a bivalent radical selected from a bond, —(C₁₋₆ alkylene)-, —(C₂₋₆alkenylene)-, or —(C₂₋₆ alkynylene)-, —(C₃₋₁₀ heterocycloalkylene)-,—(C₆₋₁₄ arylene)-, -(5- to 14-membered heteroarylene)-;

R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at eachoccurrence, H or C₁₋₆ alkyl;

n is 1 or 2;

p is 0, 1, 2, or 3; and

r is 0, 1, 2, or 3.

In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—, substituted orunsubstituted C₀₋₃ alkylene-C(═O)—, substituted or unsubstituted C₀₋₃alkylene-C(═N—OH)—, substituted or unsubstituted C₀₋₃alkylene-(C(═O)NR₅)—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-O—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted or unsubstituted C₀₋₃alkylene-S(═O)₂N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃ alkylene-C(═O)—,substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstitutedC₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—,substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂N(R₅)—, or substituted orunsubstituted C₀₋₃ alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ issubstituted or unsubstituted C₁₋₃ alkylene, substituted or unsubstitutedC₀₋₃ alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃alkylene-C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—.In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-O—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-O—, or substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. Insome embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene orsubstituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—,substituted or unsubstituted C₀₋₃ alkylene-C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted or unsubstitutedC₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, orsubstituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))— orsubstituted or unsubstituted C₀₋₃ alkylene-C(═O)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—.

In one embodiment of Formula V, R₆ and R₇ are each independently, ateach occurrence, —OH, —NH₂, —CN, —NO₂, —C(═O)OR^(b), —C(═O) N(R^(b))₂,—N(R^(b))C(═O)OR^(b), halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or ═O.

In another embodiment of Formula V, R₅ is H, C₁₋₆ alkyl, —(C₁₋₄alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄ alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl).

In yet another aspect, the disclosure provides a compound of Formula VI:

or a pharmaceutically acceptable salt thereof,

wherein:

R₁ is H, C₁₋₆ alkyl, —OH, —NH₂, or SH;

R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy;

R₃ is H, C₁₋₆ alkyl, —OH, —NH₂, or SH;

R₆ and R₇ are each independently, at each occurrence, —OH, —NH₂, —CN,—NO₂, —C(═O)OR^(b), —C(═O) N(R^(b))₂, —N(R^(b))C(═O)OR^(b), halo, C₁₋₆alkyl, C₁₋₆ alkoxy, ═O, an optionally substituted alkyl, an optionallysubstituted heteroalkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl or an optionally substituted alkoxy;

ring R is C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, or a 5-to 14-membered heteroaryl;

ring T is C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, or a 5-to 14-membered heteroaryl;

X is C(H), S, or N;

Z is O or S;

L₁ is a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—,—OC(═O)—, —(C(═O)NR^(b))—, —N(R^(b))C(═O)—, —N(R^(b))—, —S(═O)₂—, —(C₁₋₄alkylene)-, —(C₁₋₄ alkylene)-O—, —(C₁₋₄ alkylene)-N(R^(b))—, —(C₁₋₄alkylene)-S—, or —(C₁₋₄ alkylene)-S(═O)₂—;

L₂ is a bivalent radical selected from —(C(R₄)(R₅)_(n)—(C₀₋₃ alkylene)-,—(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-C(═O)—, —(C(R₄)(R₅)_(n)—(C₀₋₃ alkylene)-C(═N—OH)—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-(C(═O)NR₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-O—,—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—, —(C(R₄)(R₅)_(n)—(C₀₋₃alkylene)-S(═O)₂—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-S(═O)₂N(R₅)—, or—(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)S(═O)₂—;

wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and

each R₅ is independently H, an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₁₋₆ heteroalkyl, an optionally substituted C₁₋₆alkenyl, an optionally substituted C₁₋₆ alkynyl, an optionallysubstituted C₆₋₁₄ aryl, an optionally substituted 5- to 14-memberedheteroaryl, an optionally substituted C₃-C₈ cycloalkyl, on optionallysubstituted —(C₀₋₄ alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene),—(C₀₋₄ alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄ alkylene)-halo,—(C₀₋₄ alkylene)-NO₂, —(C₀₋₄ alkylene)-N(R^(f))₂, —(C₀₋₄alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄ alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl), —(C₀₋₄alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄ alkylene)-NR^(b)C(═O)R^(f);

wherein each R^(f) is independently H, an optionally substituted alkyl,an optionally substituted heteroalkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl or an optionallysubstituted alkoxy;

L₃ is a bivalent radical selected from a bond, —(C₁₋₆ alkylene)-, —(C₂₋₆alkenylene)-, or —(C₂₋₆ alkynylene)-, —(C₃₋₁₀ heterocycloalkylene)-,—(C₆₋₁₄ arylene)-, -(5- to 14-membered heteroarylene)-;

R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at eachoccurrence, H or C₁₋₆ alkyl;

n is 1 or 2;

p is 0, 1, 2, or 3; and

r is 0, 1, 2, or 3.

In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—, substituted orunsubstituted C₀₋₃ alkylene-C(═O)—, substituted or unsubstituted C₀₋₃alkylene-C(═N—OH)—, substituted or unsubstituted C₀₋₃alkylene-(C(═O)NR₅)—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-O—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted or unsubstituted C₀₋₃alkylene-S(═O)₂N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃ alkylene-C(═O)—,substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstitutedC₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—,substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—, substituted orunsubstituted C₀₋₃ alkylene-S(═O)₂N(R₅)—, or substituted orunsubstituted C₀₋₃ alkylene-N(R₅)S(═O)₂—. In some embodiments, L₂ issubstituted or unsubstituted C₁₋₃ alkylene, substituted or unsubstitutedC₀₋₃ alkylene-(C—OR^(c))—, substituted or unsubstituted C₀₋₃alkylene-C(═O)—, substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-O—, substituted or unsubstituted C₀₋₃alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—.In some embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene,substituted or unsubstituted C₀₋₃ alkylene-O—, substituted orunsubstituted C₀₋₃ alkylene-N(R₅)—, or substituted or unsubstituted C₀₋₃alkylene-S(═O)₂—. In some embodiments, L₂ is substituted orunsubstituted C₁₋₃ alkylene, substituted or unsubstituted C₀₋₃alkylene-O—, or substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. Insome embodiments, L₂ is substituted or unsubstituted C₁₋₃ alkylene orsubstituted or unsubstituted C₀₋₃ alkylene-N(R₅)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))—,substituted or unsubstituted C₀₋₃ alkylene-C(═O)—, substituted orunsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—, substituted or unsubstitutedC₀₋₃ alkylene-N(R₅)C(═O)—, substituted or unsubstituted C₀₋₃alkylene-O—, substituted or unsubstituted C₀₋₃ alkylene-N(R₅)—, orsubstituted or unsubstituted C₀₋₃ alkylene-S(═O)₂—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C—OR^(c))— orsubstituted or unsubstituted C₀₋₃ alkylene-C(═O)—. In some embodiments,L₂ is substituted or unsubstituted C₀₋₃ alkylene-(C(═O)NR₅)—,substituted or unsubstituted C₀₋₃ alkylene-N(R₅)C(═O)—.

In some embodiments of Formula V or of Formula VI, Z is O. In anotherembodiment of Formula V or of Formula VI, Z is S. In still anotherembodiment, X is N. In yet another embodiment, L₁ bivalent radicalselected from a bond, —(C₁₋₄ alkylene)-O—, —(C₁₋₄ alkylene)-N(R^(b))—,—(C₁₋₄ alkylene)-S—, or —(C₁₋₄ alkylene)-S(═O)₂—; R₂ is H, —OR^(a),—N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy; and R^(b) is H or C₁₋₆ alkyl. Inone embodiment, R₅ is not hydrogen. In another embodiment, R₅ is —(C₀₋₄alkylene)-OR^(f), —(C₀₋₄ alkylene)-N(R^(f))₂, —(C₀₋₄alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄ alkylene)-(C₆₋₁₄ aryl), or —(C₀₋₄alkylene)-(5- to 14-membered heteroaryl). In certain embodiments, R₅ is—(C₀₋₄ alkylene)-OR^(f), —(C₀₋₄ alkylene)-N(R^(f))₂, or —(C₀₋₄alkylene)-S(═O)₂—(R^(f)). In yet another embodiment, L₃ is a bivalentradical selected from —(C₂₋₆ alkenylene)-, —(C₂₋₆ alkynylene)-, —(C₃₋₁₀heterocycloalkylene)-, —(C₆₋₁₄ arylene)-, or -(5- to 14-memberedheteroarylene)-. In still another embodiment, L₃ is a bond. In yetanother embodiment, p is 1, and R₆ is ═O. In a further embodiment, ringR with one R₆ substituent forms a pyridinone ring (p is 1, and R₆ is═O). In some embodiments, ring R with one R₆ substituent forms a2-pyridinone ring.

In one embodiment of Formula VI, R₆ and R₇ are each independently, ateach occurrence, —OH, —NH₂, —CN, —NO₂, —C(═O)OR^(b), —C(═O) N(R^(b))₂,—N(R^(b))C(═O)OR^(b), halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or ═O.

In another embodiment of Formula VI, R₅ is H, C₁₋₆ alkyl, —(C₁₋₄alkylene)-OR^(d), —(C₁₋₄ alkylene)-N(R^(d))₂, —(C₁₋₄alkylene)-S(═O)₂—(R^(d)), —(C₁₋₄ alkylene)-(C₆₋₁₄ aryl), or —(C₁₋₄alkylene)-(5- to 14-membered heteroaryl).

In yet another aspect, the disclosure provides compounds having thestructural formulas provided in Table 1.

TABLE 1 Select compounds of the disclosure. Compound ID No. Structure 70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

110

111

112

113

114

Pharmaceutical Compositions

As used herein the term “pharmaceutical composition” refers to apreparation of one or more of the components described herein, orpharmaceutically acceptable salts thereof, with other chemicalcomponents such as physiologically suitable carriers and excipients. Thepurpose of a pharmaceutical composition is to facilitate administrationof a compound to a patient or subject.

The term “excipient” refers to an inert or inactive substance added to apharmaceutical composition to further facilitate administration of acompound. Non-limiting examples of excipients include calcium carbonate,calcium phosphate, various sugars and types of starch, cellulosederivatives, gelatin, vegetable oils and polyethylene glycols.

The present teachings further comprise pharmaceutical compositionscomprising one or more of the compounds of the present disclosure, andat least one pharmaceutically acceptable excipient.

In some embodiments, compositions are administered to humans, humanpatients or subjects. For the purposes of the present disclosure, thephrase “active ingredient” generally refers to a compound to bedelivered as described herein.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to any other animal, e.g., to non-human animals, e.g.non-human mammals. Subjects to which administration of thepharmaceutical compositions is contemplated include, but are not limitedto, non-human mammals, including cattle, pigs, cats, dogs, mice, andrats.

Dosing

The present disclosure provides methods comprising administeringcompounds of the disclosure to a subject in need thereof. Metalloproteinmodulator compounds as described herein may be administered to a subjectusing any amount and any route of administration effective for treatinga disease, a disorder, or a condition (e.g., a disease, a disorder, or acondition relating to gram-negative bacterial infections).

Compositions in accordance with the disclosure are typically formulatedin dosage unit form for ease of administration and uniformity of dosage.It will be understood, however, that the total daily usage of thecompositions of the present disclosure may be decided by the attendingphysician within the scope of sound medical judgment. The specifictherapeutically effective or prophylactically effective dose level forany particular subject will depend upon a variety of factors includingthe species, age, body weight, general health, sex and diet of thesubject; the disorder or disease being treated and the severity of thedisorder or disease; the activity of the specific compound employed; thespecific composition employed; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

Use of Metalloprotein Modulators

Metalloproteins influence a vast diversity of biological systems,biological processes, and diseases. For example, LpxC, a zinc-dependentdeacetylase, catalyzes the first committed step in Lipid A biosynthesis.Lipid A is an essential component of the outer membrane of gram-negativebacteria. LpxC is highly conserved across strains of gram-negativebacteria. Therefore, inhibitors of LpxC may provide effectivealternative antibacterial agents.

In another aspect, the disclosure provides a method of modulating theactivity of a metalloprotein such as LpxC in a subject in need thereofcomprising administering to the subject a metalloprotein modulatorcomprising a hydroxypyridinone or hydroxypyrimidinone derivative. Thehydroxypyridinone or hydroxypyrimidinone will bind to the catalyticzinc(II) ion and inhibit LpxC. LpxC has been implicated in diseasesincluding bacterial infection. In some embodiments, the gram-negativebacterial infection is a urinary tract infection, a hospitalacquired/ventilator-associated pneumonia, or an intra-abdominalinfection.

In another aspect, the disclosure provides a method for treating orameliorating one or more diseases associated with a metalloproteinfunction or activity comprising administering a therapeutically effectamount of a metalloprotein modulator. In some embodiments, themetalloprotein modulator inhibits the activity of a metalloprotein,LpxC.

In another embodiment, the LpxC inhibitor is a compound of Formula I, acompound of Formula II, a compound of Formula III, a compound of FormulaIV, a compound of Formula V, or a compound of Formula VI.

In still another aspect, the disclosure provides a method of modulatingthe activity of LpxC in a subject in need thereof comprisingadministering a therapeutically effective amount of a compound ofFormula I, a compound of Formula II, a compound of Formula III, acompound of Formula IV, a compound of Formula V, a compound of FormulaVI, or a pharmaceutically acceptable salt thereof.

In another embodiment, methods of treatment to treat or to ameliorate agram-negative bacterial infection are provided. The compounds of thedisclosure can be used for treating conditions caused by the bacterialproduction of endotoxin and, in particular, by gram-negative bacteriaand bacteria that use LpxC in the biosynthesis of lipopolysaccharide(LPS) or endotoxin. In some embodiments, the method of treating agram-negative bacterial infection in a subject comprises administeringto the subject a pharmaceutical composition comprising a compound ofFormula I, a compound of Formula II, a compound of Formula III, acompound of Formula IV, a compound of Formula V, a compound of FormulaVI, or a pharmaceutically acceptable salt thereof.

One embodiment provided herein describes the use of a compound ofFormula I, a compound of Formula II, a compound of Formula III, acompound of Formula IV, a compound of Formula V, a compound of FormulaVI, or a pharmaceutically acceptable salt thereof in the manufacture ofa medicament. Another embodiment provided herein describes a compound ofFormula I, a compound of Formula II, a compound of Formula III, acompound of Formula IV, a compound of Formula V, a compound of FormulaVI, or a pharmaceutically acceptable salt thereof for use as amedicament. In some embodiments, the medicament is used for thetreatment of a bacterial infection. In some embodiments, the medicamentis used for the treatment of a gram-negative bacterial infection.

In yet another embodiment, the compounds of the disclosure also areuseful in the treatment of patients suffering from or susceptible topneumonia, sepsis, cystic fibrosis, intra-abdominal infection, skininfections or urinary tract infections.

In yet another embodiment, the compounds of the disclosure also areuseful in the treatment of patients suffering from chronic urinary tractinfections, complicated urinary tract infections, cystitis,pyelonephritis, urethritis, recurrent urinary tract infections, bladderinfections, urethral infections or kidney infections. In someembodiments, the compounds described herein are used for the treatmentof complicated urinary tract infections.

In another embodiment, the compounds of the disclosure also are usefulin the treatment of patients suffering from complicated intra-abdominalinfection, peritonitis, intra-abdominal abscesses, diverticulitis,appendicitis, antibiotic associated diarrhea or intra-abdominal sepsis.In certain embodiments, the compounds described herein are used fortreating chronic intra-abdominal infection.

In other embodiments, the compounds of the disclosure also are useful inthe treatment of patients suffering from hospital acquired pneumonia,ventilator associated pneumonia, healthcare-associated pneumonia,community-acquired pneumonia or nosocomial pneumonia. In certainembodiments, the compounds described herein are used for treatinghospital acquired pneumonia and ventilator associated pneumonia.

In still another embodiment, the compounds of the disclosure also areuseful in the conditions that are caused or exacerbated by the bacterialproduction of lipid A and LPS or endotoxin, such as sepsis, septicshock, systemic inflammation, localized inflammation, chronicobstructive pulmonary disease (COPD) and acute exacerbations of chronicbronchitis (AECB).

In other embodiments, the compounds of the disclosure can be used forthe treatment of a serious or chronic respiratory tract or complicatedurinary tract infections including serious lung and nosocomialinfections such as those caused by Enterobacter aerogenes, Enterobactercloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca,Proteus mirabilis, Serratia marcescens, Stenotrophomonas maltophilia,Pseudomonas aeruginosa, Burkholderia cepacia, Acinetobacter baumannii,Alcaligenes xylosoxidans, Flavobacterium meningosepticum, Providenciasluarlii and Citrobacter freundi, community lung infections such asthose caused by Haemophilus influenzae, Legionella species, Moraxellacatarrhalis, Enterobacter species, Acinetobacter species, Klebsiellaspecies, Burkholderia species, and Proteus species, and infectionscaused by other bacterial species such as Neisseria species, Shigellaspecies, Salmonella species, Helicobacler pylori, Vibrionaceae andBordetella species as well as the infections caused by a Brucellaspecies, Francisella tularensis and/or Yersinia pestis.

Inhibited Metalloproteins

This disclosure includes complexes of bacterial metalloproteinsreversibly bound or chelated to any of the compounds of Formula I,Formula II, Formula III, Formula IV, Formula IVA, Formula IVB, FormulaV, Formula VI, or a deprotonated analogue thereof. The aforementionedcomplex has reduced or no catalytic activity as compared to thenon-complexed metalloprotein.

Also described herein are inhibited metalloprotein enzymes. In oneembodiment, the metalloprotein comprises zinc. In one embodiment, themetalloprotein is UDP-{3-O—[(R)-3-hydroxymyristoyl]}-N-acetylglucosaminedeacetylase (LpxC). Also described herein are reversible inhibitors ofLpxC. Further described are reversible inhibitors of LpxC that bond orcoordinate via one or more bonds to the zinc metal center.

Some embodiments provided herein describe reversible inhibitors of otherdeacetylase metalloproteins, wherein the other deacetylasemetalloprotein share homology with LpxC by having a zinc ion metalcenter that can form a coordinate bond with the reversible inhibitor.Also described herein are methods for synthesizing such reversibleinhibitors, methods for using such reversible inhibitors in thetreatment of diseases (including diseases wherein reversible inhibitionof LpxC provides therapeutic benefit to a patient having a bacterialinfection).

Also provided herein in some embodiments is a metalloprotein complexedto a pyridinone or pyrimidinone. In some embodiments, the metalloproteinis complexed to a hydroxypyridinone or hydroxypyrimidinone. In someembodiments, the metalloprotein is complexed to the inhibitor (e.g.,hydroxypyridinone or hydroxypryimidinone) in different motifs. In someembodiments, the complexed metalloprotein is an inhibited enzyme. Insome embodiments, the pyridinone or pyrimidinone complexed to themetalloprotein is a compound described herein. In certain embodiments,the pyridinone or pyrimidinone complexed to the metalloprotein is acompound having the structure of Formula I, Formula II, Formula III,Formula IV, Formula IVA, Formula IVB, Formula V, Formula VI, or apharmaceutically acceptable salt, solvate, ester, acid or prodrugthereof.

In one embodiment, provided herein is a complex of an inhibited enzymeof Formula (A):M-I  Formula (A)wherein:

M is a metalloprotein;

I is an inhibitor.

In some embodiments, the inhibitor is a non-hydroxamic acid compound. Insome embodiments, the inhibitor is a pyridinone or pyrimidinone. In someembodiments, the inhibitor is a hydroxypyridinone orhydroxypyrimidinone. In certain embodiments, the inhibitor is a compounddescribed herein. In some embodiments, the inhibitor is a compoundhaving the structure of Formula I, Formula II, Formula III, Formula IV,Formula IVA, Formula IVB, Formula V, Formula VI, or a pharmaceuticallyacceptable salt, solvate, ester, acid or prodrugs thereof.

In one embodiment, inhibitor is bound, attached or chelated to themetalloprotein in different motifs. In one embodiment of a complex ofFormula A, M and I are attached by at least one bond. In anotherembodiment, M and I are attached by at least one coordinate bond. Inanother embodiment, M and I are attached by at least two coordinatebonds. In another embodiment, M and I are attached by at least onehydrogen bond. In another embodiment, M and I are attached by at leastone ionic or electrostatic bond. In another embodiment, M and I areattached by both coordinate and hydrogen bonds. In one embodiment, M andI are attached by at least two coordinate bonds and at least onehydrogen bond. In one embodiment, M and I are attached by at least twocoordinate bonds and at least one hydrogen bond.

In one embodiment, M is a metalloprotein whose metal ion is chelated,attached or bound to one or more amino acids. In some embodiments, theamino acid chelated, attached, or bound to the metal ion is histidine,lysine, aspartate, threonine, aromatic phenyl alanine (e.g.,phenylalanine, tryptophan, or tyrosine), glycine, glutamine, leucine,glutamate, or cysteine. In some embodiments, the amino acid chelated,attached, or bound to the metal ion is histidine, lysine, aspartate,threonine, aromatic phenyl alanine, glycine, glutamine, or leucine. Insome embodiments, the amino acid chelated, attached, or bound to themetal ion is histidine, lysine, glutamate or aspartate. In someembodiments, the amino acid chelated, attached, or bound to the metalion is histidine. In some embodiments, the amino acid chelated,attached, or bound to the metal ion is lysine. In some embodiments, theamino acid chelated, attached, or bound to the metal ion is aspartate.In some embodiments, the amino acid chelated, attached, or bound to themetal ion is glutamate.

In one embodiment, the metal ion of the inhibited metalloprotein ischelated, attached or bound to one or more amino acids selected from thegroup consisting of histidine, lysine, aspartate, threonine, aromaticphenyl alanine (e.g., phenylalanine, tryptophan, or tyrosine), glycine,glutamine, leucine, glutamate, and cysteine. In another embodiment, themetal ion of the metalloprotein is chelated, attached or bound to one ormore amino acids selected from the group consisting of histidine,lysine, aspartate, threonine, aromatic phenyl alanine (e.g.,phenylalanine, tryptophan, or tyrosine), glycine, glutamine, andleucine. In another embodiment, the metal ion of the metalloprotein ischelated, attached or bound to one or more amino acids selected from thegroup consisting of histidine, lysine, and aspartate. In one embodiment,the metal ion of the inhibited metalloprotein is chelated, attached orbound to at least two amino acids selected from the group consisting ofhistidine, lysine, aspartate, threonine, aromatic phenyl alanine (e.g.,phenylalanine, tryptophan, or tyrosine), glycine, glutamine, leucine,glutamate, and cysteine. In another embodiment, the metal ion of themetalloprotein is chelated, attached or bound to at least two aminoacids selected from the group consisting of histidine, lysine,aspartate, threonine, aromatic phenyl alanine (e.g., phenylalanine,tryptophan, or tyrosine), glycine, glutamine, and leucine. In anotherembodiment, the metal ion of the metalloprotein is chelated, attached orbound to at least two amino acids selected from the group consisting ofhistidine, lysine, and aspartate. In one embodiment, the metal ion ofthe inhibited metalloprotein is chelated, attached or bound to at leastthree amino acids selected from the group consisting of histidine,lysine, aspartate, threonine, aromatic phenyl alanine (e.g.,phenylalanine, tryptophan, or tyrosine), glycine, glutamine, leucine,glutamate, and cysteine. In another embodiment, the metal ion of themetalloprotein is chelated, attached or bound to at least three aminoacids selected from the group consisting of histidine, lysine,aspartate, threonine, glutamate, aromatic phenyl alanine (e.g.,phenylalanine, tryptophan, or tyrosine), glycine, glutamine, andleucine. In another embodiment, the metal ion of the metalloprotein ischelated, attached or bound to histidine, cysteine, glutamate andaspartate.

In one embodiment, the metal ion of the inhibited metalloprotein iscoordinated, attached or bound to one or more amino acids through theheteroatom of the amino acid, namely oxygen, sulfur or nitrogen.

In one embodiment, M is an LpxC metalloprotein. In certain embodiments,the inhibitor I can be bound, chelated or attached to M and results inthe reduction of enzymatic activity. In one embodiment, I is bound tothe zinc metal ion in the enzyme LpxC. In another embodiment, I is boundto the zinc metal ion in LpxC through one or more bonds originating fromthe oxygen, nitrogen or sulfur atoms present in the composition of theinhibitor I. In an additional embodiment, inhibitor I is bound to thezinc metal ion in LpxC while inhibitor I is also bound to at least oneamino acid residue present in the enzyme through one or more coordinateor hydrogen bonds.

In one embodiment, M has the structure of Formula A-I:

wherein each AA is one or more amino acids; and

n is 0, 1, 2, 3 or 4.

In one embodiment, M has the structure of Formula A-II:

wherein each AA is one or more amino acids; and

n is 0, 1, 2 or 3.

In one embodiment, M has the structure of Formula A-III:

wherein each AA is one or more amino acids.

In one embodiment, a complex of Formula A, A-I, A-II, or A-III resistsdissociation due to bonding, chelation or attachment between M and I. Inan additional embodiment, a complex Formula A resists dissociation dueto the shape of the binding pocket present in the metalloprotein. Inanother embodiment, a complex of Formula A resists dissociation due toelectrostatic interactions present between M and I. In one embodiment,inhibitor I is bound, attached, or chelated to M with one or more bonds.In another embodiment, inhibitor I is bound, attached, or chelated to Mwith two or more bonds. In one embodiment, inhibitor I is bound,attached, or coordinated to M with one bond. In another embodiment,inhibitor I is bound, attached, or chelated to M with two bonds.

In one embodiment, inhibitor I is a compound of Formula I, Formula II orFormula III, wherein R₃ is —OH and Z is O or S. The inhibitor I isbound, attached or chelated to M with one or more coordinate bonds. Inone embodiment, inhibitor I is coordinated, attached or chelated to themetal center.

In another embodiment, wherein inhibitor I is a compound of Formula I,Formula II or Formula III, and R₃ is —OH and Z is O or S, themetalloprotein M is the enzyme LpxC possessing a zinc metal center. Oneor both of R₃ and Z can be optionally bound to the zinc metal center ofLpxC, correlating to a decrease in the enzymatic activity of M whencompared to that of uninhibited M.

In one embodiment, inhibitor I is a compound of Formula IV, Formula IVA,Formula IVB, Formula V or Formula VI. The inhibitor I is bound, attachedor chelated to M with one or more bonds. In one embodiment, the bondsare attached to the metal center.

In one embodiment, wherein inhibitor I is a compound of Formula IV,Formula IVA, Formula IVB, Formula V or Formula VI, inhibitor I is boundto M through the non-variable adjacent oxygen atoms present on thesubstituted heterocyclic ring of any of the compounds of Formulas IV,IVA, IVB, V or VI. In an embodiment in which M is the metalloproteinLpxC, one or both of the non-variable adjacent oxygen atoms present onthe substituted heterocyclic ring of any of the compounds of FormulasIV, IVA, IVB, V or VI can be optionally bound to the zinc metal centerof LpxC.

In one embodiment, provided herein is a complex of an inhibited enzymeof Formula (B):

wherein:

M is a metal;

AA is one or more amino acids attached, bound or chelated to M;

Z is O or S;

Y is OH, NH₂ or SH; and

each R is independently an organic radical, and can connect to formaryl, heteroaryl, cycloalkyl or heterocycle rings.

In another embodiment, provided herein is a complex of an inhibitedenzyme of Formula (C):

wherein:

M is a metal;

AA is one or more amino acids attached, bound or chelated to M;

Z is O or S;

X is CH or N

R₁, R₂, R₃ and R₄ are each independently hydrogen or an organic radical.

In another embodiment, provided herein is a complex of an inhibitedenzyme of Formula (D):

wherein:

M is a metal;

AA is one or more amino acids attached, bound or chelated to M;

Z is O or S;

X is CH or N

Y is OH, NH₂ or SH; and

R₁, R₂ and R₄ are each independently hydrogen or an organic radical.

In another embodiment, provided herein is a complex of an inhibitedenzyme of Formula (E):

wherein:

AA is one or more amino acids attached, bound or chelated to the metalzinc;

Z is O or S;

R₂ and R₃ are each independently hydrogen or an organic radical.

In one embodiment of Formula (E), R₂ is H, —OR^(a), —N(R^(a))₂, C₁₋₆alkyl, or C₁₋₆ alkoxy; wherein R^(a), is H or C₁₋₆ alkyl. In a furtherembodiment of Formula (E), R₃ is a substituted alkyl.

In one embodiment of Formula (E), R₂ is either (a) a H or alkyl; or (b)a bivalent radical selected from a bond, —C(═O)—, —(C(═O)O)—, —OC(═O)—,—(C(═O)NR^(c))—, —N(R^(c))C(═O)—, —N(R^(c))—, —S(═O)₂—, —(C₁₋₄alkylene)-, —(C₁₋₄ alkylene)-O—, —(C₁₋₄ alkylene)-N(R^(c))—, —(C₁₋₄alkylene)-S—, or —(C₁₋₄ alkylene)-S(═O)₂— ending in a hydrogen atom oran alkyl group.

In another embodiment of Formula (E), R₃ is the chain of substituents asfollows:

wherein:

-   -   L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-(C(═O)NR₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-O—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—, —(C(R₄)(R₅))_(n)(C₀₋₃        alkylene)-S(═O)₂—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-S(═O)₂N(R₅)—, or —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)S(═O)₂—;    -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl, on optionally substituted —(C₀₋₄        alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene), —(C₀₋₄        alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄        alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄        alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted heteroalkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl or an optionally substituted alkoxy;    -   L₃ is a bivalent radical selected from —(C₂₋₆ alkenylene)- or        —(C₂₋₆ alkynylene)-;    -   L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,        —(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;    -   G₁ and G₂ are each independently, at each occurrence, a bivalent        radical selected from —(C₆₋₁₄ arylene)- or -(5- to 14-membered        heteroarylene)-;    -   G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5-        to 14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄        heteroalkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀        heterocycloalkylene)-(C₁₋₄ heteroalkyl), an optionally        substituted alkyl, an optionally substituted heteroalkyl, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted heterocyclyl, an optionally substituted aryl, an        optionally substituted heteroaryl or an optionally substituted        alkoxy;    -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl; and

n is 1 or 2.

In another embodiment, provided herein is a complex of an inhibitedenzyme of Formula (F):

wherein:

AA is one or more amino acids attached, bound or chelated to the metalzinc;

Z is O or S;

R₁, R₂ and R₃ are each independently hydrogen or an organic radical.

In one embodiment of Formula (F), R₂ and R₃ are each independently H,—OR^(a), —N(R^(a))₂, C₁₋₆ alkyl, or C₁₋₆ alkoxy; wherein R^(a), is H orC₁₋₆ alkyl. In a further embodiment of Formula F, R₁ is a substitutedalkyl.

In one embodiment of Formula (F), R₂ and R₃ are each independentlyeither (a) a H or alkyl; or (b) a bivalent radical selected from a bond,—C(═O)—, —(C(═O)O)—, —OC(═O)—, —(C(═O)NR^(c))—, —N(R^(c))C(═O)—,—N(R^(c))—, —S(═O)₂—, —(C₁₋₄ alkylene)-, —(C₁₋₄ alkylene)-O—, —(C₁₋₄alkylene)-N(R^(c))—, —(C₁₋₄ alkylene)-S—, or —(C₁₋₄ alkylene)-S(═O)₂—ending in a hydrogen atom or an alkyl group.

In another embodiment of Formula (F), R₁ is the chain of substituents asfollows:

wherein:

-   -   L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-(C(═O)NR₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-O—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-S(═O)₂—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-S(═O)₂N(R₅)—, or —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)S(═O)₂—;    -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl, on optionally substituted —(C₀₋₄        alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene), —(C₀₋₄        alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄        alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄        alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted heteroalkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl or an optionally substituted alkoxy;    -   L₃ is a bivalent radical selected from —(C₂₋₆ alkenylene)- or        —(C₂₋₆ alkynylene)-;    -   L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,        —(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;    -   G₁ and G₂ are each independently, at each occurrence, a bivalent        radical selected from —(C₆₋₁₄ arylene)- or -(5- to 14-membered        heteroarylene)-;

G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), an optionally substituted alkyl, an optionally substitutedheteroalkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl or an optionally substituted alkoxy;

-   -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl; and

n is 1 or 2.

In another embodiment, provided herein is a complex of an inhibitedenzyme of Formula (G):

wherein:

AA is one or more amino acids attached, bound or chelated to the metalzinc;

R₃ is the chain of substituents as follows:

wherein:

-   -   L₂ is a bivalent radical selected from —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-, —(C(R₄)(R₅))_(n)—C₀₋₃ alkylene)-(C—OR^(c))—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-C(═N—OH)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-(C(═O)NR₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)C(═O)—, —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-O—,        —(C(R₄)(R₅))_(n)—(C₀₋₃ alkylene)-N(R₅)—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-S(═O)₂—, —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-S(═O)₂N(R₅)—, or —(C(R₄)(R₅))_(n)—(C₀₋₃        alkylene)-N(R₅)S(═O)₂—;    -   wherein each R₄ is H or optionally substituted C₁₋₆ alkyl; and    -   each R₅ is independently H, an optionally substituted C₁₋₆        alkyl, an optionally substituted C₁₋₆ heteroalkyl, an optionally        substituted C₁₋₆ alkenyl, an optionally substituted C₁₋₆        alkynyl, an optionally substituted C₆₋₁₄ aryl, an optionally        substituted 5- to 14-membered heteroaryl, an optionally        substituted C₃-C₈ cycloalkyl, on optionally substituted —(C₀₋₄        alkylene)-OR^(f), —(C₀₋₄ alkylene)-(C₁₋₄ alkene), —(C₀₋₄        alkylene)-(C₁₋₄ alkyne), C₂-C₇ heterocycle, —(C₀₋₄        alkylene)-C(═O)—(C₁-C₆ alkyl), —(C₀₋₄ alkylene)-C(═O)H, —(C₀₋₄        alkylene)-C(═O)OR^(f), —(C₀₋₄ alkylene)-CN, —(C₀₋₄        alkylene)-halo, —(C₀₋₄ alkylene)-NO₂, —(C₀₋₄        alkylene)-N(R^(f))₂, —(C₀₋₄ alkylene)-S(═O)₂—(R^(f)), —(C₀₋₄        alkylene)-(C₆₋₁₄ aryl), —(C₁₋₄ alkylene)-(5- to 14-membered        heteroaryl), —(C₀₋₄ alkylene)-C(═O)NR^(b)R^(f) or —(C₀₋₄        alkylene)-NR^(b)C(═O)R^(f);    -   wherein each R^(f) is independently H, an optionally substituted        alkyl, an optionally substituted heteroalkyl, an optionally        substituted alkenyl, an optionally substituted alkynyl, an        optionally substituted cycloalkyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl or an optionally substituted alkoxy;    -   L₃ is a bivalent radical selected from —(C₂₋₆ alkenylene)- or        —(C₂₋₆ alkynylene)-;    -   L₄ is a bivalent radical selected from —C(═O)—, —(C(═O)O)—,        —(C(═O)NR^(e))—, —N(R^(e))C(═O)—, or —(C₁₋₄ alkylene)-;    -   G₁ and G₂ are each independently, at each occurrence, a bivalent        radical selected from —(C₆₋₁₄ arylene)- or -(5- to 14-membered        heteroarylene)-;

G₃ is H, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, 5- to14-membered heteroarylene, (C₁₋₄ alkylene)-(C₁₋₄ heteroalkyl), (C₃₋₁₀heterocycloalkylene)-(C₁₋₄ alkyl), (C₃₋₁₀ heterocycloalkylene)-(C₁₋₄heteroalkyl), an optionally substituted alkyl, an optionally substitutedheteroalkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl or an optionally substituted alkoxy;

-   -   R^(a), R^(b), R^(c), R^(d), and R^(e) are each independently, at        each occurrence, H or C₁₋₆ alkyl; and

n is 1 or 2.

Kits and Devices

The disclosure provides a variety of kits for conveniently andeffectively carrying out methods of the present disclosure. Typicallykits will comprise sufficient amounts and components to allow a user toperform multiple treatments of a subject(s) or to perform multipleexperiments. In another embodiment, the kit may contain a compound ofFormula I, a compound of Formula II, a compound of Formula III, acompound of Formula IV, a compound of Formula V, or a compound ofFormula VI.

In additional embodiments, pharmaceutical kits are provided. The kitincludes a sealed container approved for the storage of pharmaceuticalcompositions, the container containing one of the above-describedpharmaceutical compositions. In some embodiments, the sealed containerminimizes the contact of air with the ingredients, e.g. an airlessbottle. In other embodiments, the sealed container is a sealed tube. Aninstruction for the use of the composition and the information about thecomposition are to be included in the kit.

The present disclosure provides for devices which may incorporatecompounds of the present disclosure. These devices contain in a stableformulation available to be immediately delivered to a subject in needthereof, such as a human patient.

It will be appreciated that the following examples are intended toillustrate but not to limit the present disclosure. Various otherexamples and modifications of the foregoing description and exampleswill be apparent to a person skilled in the art after reading thedisclosure without departing from the spirit and scope of thedisclosure, and it is intended that all such examples or modificationsbe included within the scope of the appended claims. All publicationsand patents referenced herein are hereby incorporated by reference intheir entirety.

EXAMPLES Example 1 Synthesis of Compounds or Metalloprotein Modulators

The compounds, metalloprotein modulators or metalloprotein inhibitors ofthe present disclosure may be synthesized with standard syntheticmethods. Those skilled in the art of organic synthesis will recognizevarious synthetic methodologies that may be used to prepare compounds ormetalloprotein modulators of the present disclosure.

Unless otherwise noted, starting materials were purchased fromcommercial suppliers (e.g., Sigma-Aldrich, Chem-Bridge, and AcrosOrganics) and were used without further purification. All commercialmaterials were listed as 95% purity or greater. The purity of allsynthesized compounds was determined to be ≥95% by either elementalanalysis or HPLC. Flash silica gel chromatography was performed usingsilica gel 40-63 μm mesh. ¹H and ¹³C NMR spectra were recorded on one ofseveral Varian FT-NMR spectrometers,

In the discussion above and in the examples below, the followingabbreviations have the following meanings. If an abbreviation is notdefined, it has its generally accepted meaning.

-   -   DIAD=diisopropyl azocarboxylate    -   DMF=dimethylformamide    -   DMA=dimethylacetamide    -   DMAP=dimethylaminopyridine    -   DMSO=dimethyl sulfoxide    -   MeTHF=2-methyltetrahydrofuran    -   HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate)    -   DIPEA=N,N-Diisopropylethylamine    -   CBZ=benzyloxycarbonyl    -   DCC=1,3-dicyclohexylcarbodiimide    -   EtOAc=ethyl acetate    -   EtO=ethoxy    -   MeOH=methanol    -   DCM=dichloromethane    -   HCl=hydrochloric acid    -   ACN=acetonitrile    -   LDA=lithium diisopropylamide    -   mCPBA=meta-chloroperbenzoic acid    -   MTBE=methyl tert butyl ether    -   CDMT=2-chloro-4,6-dimethoxy-1,3,5-triazine    -   TMS=trimethyl silyl    -   DME=dimethyl ether    -   IPA=isopropanol    -   Et₂O=diethyl ether    -   DEAD=diethyl azodicarboxylate    -   LiHMDS=lithium hexamethyldisilazide/lithium        bis(trimethylsilyl)amide    -   Aq.=aqueous    -   bm=broad multiplet    -   BOC=tert-butoxy carbonyl    -   bd=broad doublet    -   bs=broad singlet    -   d=doublet    -   dd=doublet of doublets    -   dq=doublet of quartets    -   dt=doublet of triplets    -   eq.=equivalents    -   g=grams    -   h=hours    -   HPLC=high pressure liquid chromatography    -   UPLC=ultra performance liquid chromatography    -   m=multiplet    -   M=molar    -   M %=mole percent    -   max=maximum    -   meq=milliequivalent    -   mg=milligram    -   mL=milliliter    -   mm=millimeter    -   mmol=millimol    -   q=quartet    -   s=singlet    -   t or tr=triplet    -   TBS=tert-butyldimethylsilyl    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TLC=thin layer chromatography    -   p-TLC=preparative thin layer chromatography    -   μL=microliter    -   N=normality    -   MS=mass spectrometry    -   rt=room temperature    -   Ac=acetate    -   NMP=1-methyl-2-pyrrolidinone    -   μL=microliter    -   J=coupling constant    -   NMR=nuclear magnetic resonance    -   MHz=megahertz    -   Hz=hertz    -   m/z=mass to charge ratio    -   min=minutes    -   ppt=precipitate    -   sat.=saturated        Synthesis of Compounds 82, 83, 84, and 85

The synthetic scheme to prepare compounds 82, 83, 84 and 85 is shown inFIG. 1.

Synthesis of ethyl5-(benzyloxy)-1-(2-(4-bromophenyl)-2-oxoethyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate, 10

To a solution of ethyl5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate, 3 (2g, 0.0069 mol) dissolved in DMF (20 mL) was added K₂CO₃ (1.2 g, 0.009mol) and 4-bromophenacyl bromide, 9 (1.9 g, 0.0069 mol) and stirred at25° C., for 1 h. After completion of the reaction, DMF was removed underreduced pressure, the crude product was diluted with water and EtOAc.The layers were separated, the aqueous layer was extracted with EtOAcand the combined organic layers were washed with brine solution anddried over anhydrous Na₂SO₄, filtered and concentrated. The crudeproduct was triturated with cold methanol to get 1.3 g (40.6%) of pureethyl5-(benzyloxy)-1-(2-(4-bromophenyl)-2-oxoethyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,10. UPLC=Calculated for C₂₃H₂₁BrN₂O₅ 485.33, Observed=487.2.

Synthesis of ethyl1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,11

To a solution of5-(benzyloxy)-1-(2-(4-bromophenyl)-2-oxoethyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate, 10 (0.3 g, 0.00063 mol) in toluene (15 mL),phenyl boronic acid (0.23 g, 0.0018 mol), K₂CO₃ (0.17 g, 0.00126 mol)and water (3 mL) were added and degassed the reaction mixture undernitrogen for 10 min. To this purged reaction mixture PdCl₂(PPh₃)₄ (0.036g, 0.0000315 mol) was added and heated the reaction mixture to 100° C.for 3 h. After completion of the reaction, reaction mixture was cooled,diluted with EtOAc and washed with water and brine solution. The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude product was purified by columnchromatography to get 0.25 g (83%) of pure ethyl1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,11. UPLC=Calculated for C₂₉H₂₆N₂O₅ 482.54, Observed=483.2.

Synthesis of ethyl1-(2-([1,1′-biphenyl]-4-yl)-2-hydroxyethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,67 and ethyl1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,84

1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate(0.25 g, 0.000621 mol) was dissolved in 1:1 methanol (3 mL) and THF (3mL). To this 10% Palladium on carbon (25 mg) was added and hydrogenatedat 1 atm H₂ pressure for 2 h at 25° C. After completion of the reaction,the reaction mixture was filtered on celite bed and the filtrate wasconcentered to get 0.16 g of crude product which was purified by prepHPLC purification to get 0.05 g of pure ethyl1-(2-([1,1′-biphenyl]-4-yl)-2-hydroxyethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate, compound 67, and 0.048 g of ethyl1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,compound 84.

-   Compound 85 UPLC=Calculated for C₂₂H₂₂N₂O₅: 394.43, Observed=395.2-   Compound 84 UPLC=Calculated for C₂₂H₂₀N₂O₅: 392.41, Observed=393.2

Synthesis of1-(2-([1,1′-biphenyl]-4-yl)-2-hydroxyethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid, 83

Ethyl1-(2-([1,1′-biphenyl]-4-yl)-2-hydroxyethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,67 (0.04 g, 0.0001 mol) was dissolved in THF (2 mL) and water (2 mL). Tothis NaOH (0.012 g, 0.0003 mol) was added and stirred at 25° C. for 12h. After completion of the reaction, THF was removed under reducedpressure, the aqueous layer was acidified to pH 5 and stirred for 10min. The solid precipitate was filtered and washed with water anddiethylether and dried to get 0.019 g (52.7%) of pure1-(2-([1,1′-biphenyl]-4-yl)-2-hydroxyethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid compound 83. LCMS=Calculated forC₂₀H₁₈N₂O₅: 366.37, Observed=367.2

Synthesis of1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid, 82

Ethyl1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,66 (0.04 g, 0.0001 mol) was dissolved in THF (2 mL) and water (2 mL). Tothis NaOH (0.012 g, 0.0003 mol) was added and stirred at 25° C. for 12h. After completion of the reaction, THF was removed under reducedpressure, the aqueous layer was acidified to pH 5 and stirred for 10min. The solid precipitate was filtered and washed with water anddiethylether and dried to get 0.025 g (67.5%) of pure1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid, compound 82. LCMS=Calculated forC₂₀H₁₆N₂O₅: 364.36, Observed=365.2

Synthesis of Compound 91.

The synthetic scheme to prepare compound 91 is shown in FIG. 2.

Step 1: Synthesis of ethyl5-(benzyloxy)-1-(2-(4-bromophenyl)-2-oxoethyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,2

To a stirred solution of ethyl5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate, 1 (2g, 0.0069 mol) in DMF (20 mL), K₂CO₃ (1.24 g, 0.009 mol) was added andstirred for 5 min at 25° C. Then, 4-Bromophenacyl bromide (2.01 g,0.0072 mol) was added and stirred at 25° C. for 1 h. After completion ofthe reaction, DMF was removed under reduced pressure, the crude productwas diluted with water and EtOAc. The layers were separated, the aqueouslayer was extracted with EtOAc and the combined organic layers werewashed with brine solution and dried over anhydrous Na₂SO₄, filtered andconcentrated. It was purified by flash column chromatography on silicagel with gradient elution of 20-25% EtOAc in pet ether to get 1.2 g(35.92%) of ethyl5-(benzyloxy)-1-(2-(4-bromophenyl)-2-oxoethyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,2. LCMS=Calculated for C₂₃H₂₁BrN₂O₅: 485.33, Observed=486.0.

Step 2: Synthesis of ethyl1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,3

To a stirred solution of ethyl5-(benzyloxy)-1-(2-(4-bromophenyl)-2-oxoethyl)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,2 (400 mg, 0.824 mmol) in toluene (5 mL), phenyl boronic acid (150 mg,1.23 mmol), K₂CO₃ (227 mg, 1.648 mmol), water (0.4 mL) were added anddegassed for 15 min. Then, PdCl₂(PPh₃)₄ (47 mg, 0.00412 mmol) was addedand again degassed for 5 min. The contents were heated to 100° C. for 3h. After completion of the reaction, the reaction mixture wasconcentrated and the residue was diluted by water and extracted withEtOAc. The separated organic layer was washed with brine, dried oversodium sulfate and concentrated in vacuo. The crude product was purifiedby flash column chromatography on silica gel with gradient elution of40-45% EtOAc in pet ether to get 280 mg (70.52%) of ethyl1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,3. LCMS=Calculated for C₂₉H₂₆N₂O₅: 482.54, Observed=483.1.

Step 3: Synthesis of1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylicacid, 4

To a stirred solution of ethyl1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,3 (250 mg, 0.518 mmol) in THF (5 mL), sodium hydroxide (62 mg, 1.55mmol) and water (1 mL) were added and refluxed at 70° C. for 3 h. Aftercompletion of reaction the reaction mixture was concentrated and dilutedwith water. It was acidified (pH=5) with 1.5N HCl to get the precipitatewhich was filtered, dried to obtain 170 mg (72.35%) of1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylicacid, 4. LCMS=Calculated for C₂₇H₂₂N₂O₅ 454.48, Observed=455.0.

Step 4: Synthesis of1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-(benzyloxy)-N,2-dimethyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide,5

To a stirred solution of1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylicacid, 4 (170 mg, 0.374 mmol) in DCM (4 mL), pentafluoro phenol (68 mg,0.374 mmol), DCC (115 mg, 0.561 mmol) were added and stirred at 25° C.for 1 h. Methylamine in THF (1 mL) was then added and stirred at 25° C.for 2 h. After completion of reaction, the reaction mixture wasconcentrated to get the crude product which was purified by flash columnchromatography on silica gel with gradient elution of 3% methanol indichloromethane to obtain 100 mg (57.47%) of1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-(benzyloxy)-N,2-dimethyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide,5. UPLC=Calculated for C₂₈H₂₅N₃O₄: 467.53, Observed=468.3.

Step 5: Synthesis of1-(2-([1,1′-biphenyl]-4-yl)-2-hydroxyethyl)-5-hydroxy-N,2-dimethyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide,91

To a stirred solution of1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-(benzyloxy)-N,2-dimethyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide,5 (100 mg, 0.213 mmol) in methanol: THF(1:1=3 ml), Pd/C (25 mg) wasadded and stirred at 25° C. for 5 h under H₂ balloon pressure (15 psi).After completion of reaction by UPLC, it was filtered through celite bedusing 50% methanol in dichloromethane and concentrated in vacuo. It waspurified by trituration with acetonitrile, THF and finally methanol washto obtain 30 mg (37.5%) of pure1-(2-([1,1′-biphenyl]-4-yl)-2-hydroxyethyl)-5-hydroxy-N,2-dimethyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide, compound 91. LCMS=Calculated for C₂₁H₂₁N₃O₄:379.42, Observed=380.3.

Synthesis of Compound 95.

The synthetic scheme to prepare compound 95 is shown in FIG. 3.

Step 2a: Synthesis of ethyl(E)-1-(2-([1,1′-biphenyl]-4-yl)-2-(hydroxyimino)ethyl)-5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,6

To a stirred solution of ethyl1-(2-([1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,3 (300 mg, 0.622 mmol) in ethanol (8 mL), hydroxylamine hydrochloride(86 mg, 1.244 mmol), sodium acetate (102 mg, 1.244 mmol) were added andrefluxed at 90° C. for 12 h. After completion of reaction, the solventwas removed under reduced pressure, the crude product was diluted withwater and EtOAc. The layers were separated, the aqueous layer wasextracted with EtOAc, and the combined organic layers were washed withbrine solution and dried over anhydrous Na₂SO₄, filtered andconcentrated to obtain 270 mg (87.37%) of ethyl(E)-1-(2-([1,1′-biphenyl]-4-yl)-2-(hydroxyimino)ethyl)-5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate, 6. UPLC=Calculated for C₂₉H₂₇N₃O₅: 497.55,Observed=498.3.

Step 3a: Synthesis of ethyl(E)-1-(2-([1,1′-biphenyl]-4-yl)-2-(hydroxyimino)ethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,7

To a stirred solution of(E)-1-(2-([1,1′-biphenyl]-4-yl)-2-(hydroxyimino)ethyl)-5-(benzyloxy)-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate, 6 (270 mg, 0.543 mmol) in dichloromethane (6mL), cooled to 0° C., boron trichloride (0.5 mL) was added and stirredat 25° C. for 1 h. After completion of reaction the reaction mixture wasquenched by methanol and concentrated in vacuo to obtain 100 mg (45.24%)of ethyl(E)-1-(2-([1,1′-biphenyl]-4-yl)-2-(hydroxyimino)ethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,7. UPLC=Calculated for C₂₂H₂₁N₃O₅: 407.43, Observed=408.2.

Step 4a: Synthesis of(E)-1-(2-([1,1′-biphenyl]-4-yl)-2-(hydroxyimino)ethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylicacid, 95

To a stirred solution of ethyl(E)-1-(2-([1,1′-biphenyl]-4-yl)-2-(hydroxyimino)ethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,7 (100 mg, 0.245 mmol) in THF (3 mL), sodium hydroxide (19 mg, 0.491mmol) was added and refluxed at 70° C. for 3 h. After completion ofreaction the reaction mixture was concentrated and diluted with waterand quenched by 1.5 N HCl to get solid precipitate. The precipitate wasfiltered and purified by preparative HPLC to obtain(E)-1-(2-([1,1′-biphenyl]-4-yl)-2-(hydroxyimino)ethyl)-5-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylicacid, compound 95. LCMS=Calculated for C₂₀H₁₇N₃O₅: 379.37,Observed=380.0.

Synthesis of Compound 70

The synthetic scheme to prepare compound 70 is shown in FIG. 4.

Synthesis of ethyl 2-((tetrahydro-2H-pyran-2-yl)oxy)acetate, 2

To a solution of ethyl glycolate (10 g, 0.0961 mol) in toluene (100 mL)was added 3,4-dihydro-2H-pyran (8 g, 0.0961 mol) followed by catalyticamount of pTSA (30 mg) and stirred at 25° C. for 1 h. After completionof the reaction, the reaction mixture was washed with water and brinesolution. The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure to get 18 g (99%) ethyl2-((tetrahydro-2H-pyran-2-yl)oxy)acetate, 2, as colorless liquid.

Synthesis of 2-(4-iodophenoxy)acetonitrile, 4

To a slurry of Cs₂CO₃ (11.1 g, 0.034 mol) and 4-iodophenol, 3 (5 g,0.0227 mol) in DMF (50 mL), bromoacetonitrile (3.27 g, 0.0272 mol) wasadded and stirred at 25° C. for 2 h. After completion of the reaction,the reaction mixture was filtered and concentrated under reducedpressure. The crude product was dissolved in EtOAc and washed with waterand brine solution. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated to get 5.6 g (98%) of pure2-(4-iodophenoxy)acetonitrile, 4, as an off white solid. LCMS=Calculatedfor C₈H₆INO: 259.05, Observed=257.9.

Synthesis of 2-(4-iodophenoxy)acetimidamide hydrochloride, 5

To a solution of 2-(4-iodophenoxy)acetonitrile, 4 (4.2 g, 0.0162 mol) inmethanol (40 mL), NaOMe(25% in MeOH, 3.4 mL, 0.0161 mol) was added at25° C. and stirred for 6 h. After completion of the reaction, NH₄Cl(0.95 g, 0.0177 mol) was added to the reaction mixture and heated to 50°C. for 4 h. After completion of the reaction, methanol was removed underreduced pressure. The crude product was washed with diethylether anddried to get 4.6 g (92%) of pure 2-(4-iodophenoxy)acetimidamidehydrochloride, 5 as an off white solid. LCMS=Calculated for C₈H₁₀ClN₂O:312.54, Observed=276.8.

Synthesis of2-((4-iodophenoxy)methyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyppyrimidin-4(3H)-one,6

To a cooled solution of ethyl 2-((tetrahydro-2H-pyran-2-yl)oxy)acetate,2 (2 g, 0.0106 mol) in diethyl ether (20 mL), LDA (1M in THF, 6.3 mL,0.0063 mmol) was added slowly at −78° C. and allowed to stir at 25° C.for 1 h. After completion of the reaction, reaction mixture was quenchedwith saturated NH₄Cl and reaction mixture was diluted with EtOAc andwater. The layers were separated and aqueous layer was extracted withEtOAc, combined organic layers were washed with brine solution. Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude product was dissolved in ethanol. Tothis mixture 2-(4-iodophenoxy)acetimidamide hydrochloride, 5 (6.6 g,0.021 mol) and NaOEt (21% in ethanol, 6.8 mL, 0.021 mol) were added andheated to reflux for 2 h. After completion of the reaction, solvent wasremoved under reduced pressure. The crude product was dissolved in EtOAcand washed with water and brine solution. The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated. The crude product waspurified by column chromatography using dichloromethane and 1-8% ofmethanol and to get 1.2 g (20.8%) pure2-((4-iodophenoxy)methyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrimidin-4(3H)-one, 6 as an off white solid. UPLC=Calculated forC₂₂H₂₇IN₂O₆: 542.37, Observed=543.2.

Synthesis of5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-2-((4-((trimethylsilyl)ethynyl)phenoxy)methyl)pyrimidin-4(3H)-one,7

To a solution of2-((4-iodophenoxy)methyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyppyrimidin-4(3H)-one,6 (0.5 g, 0.00092 mol) in DMF (5 mL). Triethylamine (0.27 g, 0.00276mol), CuI (0.017 g, 0.000092 mol) and PdCl₂(PPh₃)₄ (0.053 g, 0.000046mol) were added and degassed the reaction mixture under nitrogen for 10min. To this reaction mixture, trimethylsilyl acetylene (0.45 g, 0.0046mol) was added and stirred the reaction mixture at 25° C. for 16 h.After completion of the reaction, solvent was removed under reducedpressure. The crude product was dissolved in EtOAc and washed with waterand brine solution. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. The crude product was purified by columnchromatography using dichloromethane and 1-8% of methanol and to get 0.2g (42%) pure5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-2-((4-((trimethylsilyl)ethynyl)phenoxy)methyl)pyrimidin-4(3H)-one, 7 as a brown solid.UPLC=Calculated for C₂₇H₃₆N₂O₆Si: 512.68, Observed=513.4.

Synthesis of2-((4-ethynylphenoxy)methyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrimidin-4(3H)-one,8

To solution of5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-2-((4-((trimethylsilyl)ethynyl)phenoxy)methyl)pyrimidin-4(3H)-one,7 (0.2 g, 0.00039 mol) in THF (5 mL), TBAF (2M in THF, 0.39 mL, 0.00078mol) was added and stirred at 25° C. for 1 h. After completion of thereaction, reaction mixture was diluted with water and EtOAc. The layerswere separated and organic layer was washed with brine solution anddried over anhydrous Na₂SO₄, filtered and concentrated to get 0.17 g(99%) of2-((4-ethynylphenoxy)methyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrimidin-4(3H)-one,8. This crude product was directly taken for next step withoutpurification. UPLC=Calculated for C₂₄H₂₈N₂O₆: 440.50, Observed=441.4.

Synthesis of2-((4-(phenylbuta-1,3-diyn-1-yl)phenoxy)methyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrimidin-4(3H)-one,9

To a solution of2-((4-ethynylphenoxy)methyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyppyrimidin-4(3H)-one,8 (0.17 g, 0.000386 mol) in methanol (3 mL) and pyridine(3 mL) was addedphenyl acetylene(0.11 g, 0.0011 mol) followed by Cu(OAc)₂ (0.14 g,0.00077 mol) and stirred at 25° C. for 4 h. After completion of thereaction, solvent was removed under reduced pressure and the crudeproduct was dissolved in with EtOAc and washed with water and brinesolution. The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated. The crude product was purified by columnchromatography to get 0.13 g (65%) of pure2-((4-(phenylbuta-1,3-diyn-1-yl)phenoxy)methyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrimidin-4(3H)-one, 9. UPLC=Calculated for C₃₂H₃₂N₂O₆: 540.62,Observed=541.4.

Synthesis of5-hydroxy-6-((methylsulfonyl)methyl)-2-((4-(phenylbuta-1,3-diyn-1-yl)phenoxy)methyl)pyrimidin-4(3H)-one, 70

To a cooled solution of2-((4-(phenylbuta-1,3-diyn-1-yl)phenoxy)methyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyppyrimidin-4(3H)-one,9 (0.13 g, 0.00024 mol) in DCM (5 mL) SOCl₂ (5 mL) was added at 0° C.and allowed to stir at 25° C. for 2 h. After completion of the reaction,volatiles were removed under reduced pressure. To this crude productsodium methyl sulfinate was added followed by DMF (3 mL): water (3 mL),and the mixture was stirred at 25° C. for 1 h. After completion of thereaction, excess water was added to the reaction mixture and stirred for10 min. The obtained solid was filtered and washed with more water anddried. The crude solid was washed with DCM and 5% methanol to get 0.02 g(20%) pure5-hydroxy-6-((methylsulfonyl)methyl)-2-((4-(phenylbuta-1,3-diyn-1-yl)phenoxy)methyl)pyrimidin-4(3H)-one,compound 70 as an off white solid. UPLC=Calculated for C₂₃H₁₈N₂O₅S:434.47, Observed=435.2.

Synthesis of Compound 71

The synthetic scheme to prepare compound 71 is shown in FIG. 5.

Synthesis of methyl 4-((4-aminophenyl) buta-1,3-diyn-1-yl)benzoate (2)

4-ethynylaniline (5 g, 0.0426 mol) and methyl 4-ethynylbenzoate (13.6 g,0.085 mol) were taken in methanol: pyridine (100 ml: 20 ml) mixture andstirred for 15 min. Copper acetate (25.5 g, 0.128 mol) was added in oneportion and stirred the reaction mass for 3 h. After completion of thereaction, reaction mixture was concentrated, obtained crude was taken in1.5N HCl (2×100 mL) and extracted with ethyl acetate. The separatedorganic layer was dried over anhydrous Na₂SO₄ and concentrated. Theobtained crude was purified by flash chromatography over 230-400 meshcolumn silica gel with gradient elution of 2-6% ethyl acetate in petether to get 2 as light yellow solid (5.6 g). Yield: 47.8%. LC-MS and ¹HNMR confirm the required product. LCMS Calculated for C₁₈H₁₃NO₂: 275.31,Observed 276.3.

Synthesis of 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carbaldehyde (3)

5-(benzyloxy)-6-(diethoxymethyl)pyrimidin-4(3H)-one (0.6 g, 0.0019 mol)was taken in dry DCM (10 ml) and boron trichloride (1M in DCM) (6 ml)was added drop wise and stirred the reaction mass at 25° C. for 2 h.After completion of the reaction, reaction mixture was quenched withmethanol and concentrated under reduced pressure to get 3 as pale brownsolid (0.26 g). Yield: 96.2%. LC-MS and ¹H NMR confirm the requiredproduct. LCMS Calculated for C₅H₄N₂O₃: 140.10, Observed (ES) 141.2.

Methyl4-((4-(((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)amino)phenyl)buta-1,3-diyn-1-yl)benzoate,71

A suspension of 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carbaldehyde(0.06 g, 0.00042 mol) and methyl 4-((4-aminophenyl)buta-1,3-diyn-1-yl)benzoate (0.09 g, 0.00034 mol) in methanol (2 ml) andAcOH (catalytic amount, 0.06 ml) was stirred at 25° C. for 15 min.NaCNBH₄ resin was added in one portion and stirred the reaction mass for1 h. Solid precipitated out from the reaction was decanted from theresin by adding excess methanol and filtered. Solid obtained was washedwith 10% DCM in methanol (2×5 mL) to remove the unreacted amine anddried under reduced pressure to obtain compound 71 as light red solid.Yield: 0.06 g, (35.2%). LCMS Calculated for C₂₃H₁₇N₃O₄: 399.41, Observed400.1.

Synthesis of Compound 72

The synthetic scheme to prepare compound 72 is shown in FIG. 6.

Synthesis of 4-((4-aminophenyl)buta-1,3-diyn-1-yl)benzoic acid (2)

Methyl 4-((4-aminophenyl)buta-1,3-diyn-1-yl)benzoate, 1 (1 g, 0.00363mol) was taken in methanol: water (20 ml: 10 ml) mixture and NaOH (0.436g, 0.0109 mol) was added and stirred for 3 h. After completion of thereaction, reaction mixture was concentrated, the resultant crude productwas acidified with concentrated HCl (adjusted pH=2). The obtained solidwas filtered and washed with water and dried under reduced pressure get2 as light yellow solid (0.9 g). Yield: 95.7%. LC-MS and ¹H NMR confirmthe required product. MS(ES) (M+H)⁺: 262.28(M+) for C₁₇H₁₁NO₂.

Synthesis of 4-((4-aminophenyl)buta-1,3-diyn-1-yl)-N-methylbenzamide (3)

4-((4-aminophenyl)buta-1,3-diyn-1-yl)benzoic acid, 2 (0.5 g, 0.0019 mol)was taken in dry DMF (10 ml), methyl amine HCl (0.203 g, 0.0028 mol),DIPEA (0.493 g, 0.00382 mol) and HATU (1.45 g, 0.00382 mol) respectivelywere added and stirred the reaction mass for 3 h. After completion ofthe reaction, reaction mixture was concentrated and added crushed ice.The solid obtained was filtered and washed with water and dried underreduced pressure to get 3 as light orange solid (0.38 g). Yield: 73.1%.LC-MS and ¹H NMR confirm the required product. MS(ES) (M+H)⁺: 275.32(M+)for C₁₈Hl₄N₂O.

4-((4-(((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)amino)phenyl)buta-1,3-diyn-1-yl)-N-methylbenzamide,72

A suspension of 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carbaldehyde(0.3 g, 0.00214 mol) and4-((4-aminophenyl)buta-1,3-diyn-1-yl)-N-methylbenzamide, 3 (0.587 g,0.00214 mol) in methanol (5 ml) and AcOH (catalytic amount, 0.3 ml) wasstirred at 25° C. for 15 min. NaCNBH₄ resin (0.3 g) was added in oneportion and stirred the reaction mass for 1 h. The solid crashed outfrom the reaction was decanted from the resin by adding excess methanol.The decanted solid obtained was washed with 10% DCM in methanol (2×5 mL)to remove the unreacted amine and dried under reduced pressure to get 72as off white solid. (0.19 g). Yield: 20.6%. MS(ES) (M+H)⁺: 399.2(M+) forC₂₃H₁₈N₄O₃.

Synthesis of Compound 73

The synthetic scheme to prepare compound 73 is shown in FIG. 7.

Step1: Synthesis of 4,5-dimethoxypyrimidine, 2

A solution of 4-chloro-5,6-dimethoxypyrimidine, 1 (5 g, 28.64 mmol) indry methanol (100 mL) was hydrogenated at 1 atm H₂ gas pressure using Pd(10%) on carbon (1 g) as catalyst for 3 hours. After completion of thereaction, the reaction mixture was filtered through celite pad andconcentrated to dryness to get (4 g, 99%) of pure4,5-dimethoxypyrimidine, 2, as a white solid. UPLC=Calculated forC₆H₈N₂O₂ 140.14, Observed=141.1.

Step 2: Synthesis of 5-methoxypyrimidin-4(3H)-one hydrochloride, 3

A solution of 4,5-dimethoxypyrimidine, 2 (3 g, 21.41 mmol) in 6N HClsolution (30 mL) was heated at 100° C. for 16 h. After completion of thereaction, the reaction mixture was concentrated to dryness. Theoff-white residue was triturated with EtOAc (20 mL) and decanted to getpure (2.8 g, 80%) HCl salt of 5-methoxypyrimidin-4(3H)-one, 3, as anoff-white solid. LCMS Calculated for C₅H₆N₂O₂: 126.12, Observed=127.0.

Step 3: Synthesis of 3-(4-bromophenethyl)-5-methoxypyrimidin-4(3H)-one,4

To a stirred solution of 5-methoxypyrimidin-4(3H)-one hydrochloride, 3(2 g, 12.3 mmol) and 4-bromophenethyl methanesulfonate (3.4 g, 12.3mmol) in dry DMF (40 mL) was added anhydrous K₂CO₃ (5.1 g). The reactionmixture was heated at 80° C. for 2 hours. After completion of thereaction, the reaction mixture was diluted with water (30 mL), and thecrude product was extracted with EtOAc (3×20 mL). The combined organiclayer was washed with water (2×20 mL) and finally with brine solution(20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated to get crude product as a pale yellow solid which isfurther purified by automated flash column chromatography over silicagel (eluent: 90-100% EtOAc in pet ether) to obtain (800 mg, 21%)3-(4-bromophenethyl)-5-methoxypyrimidin-4(3H)-one, 4, as a white solid.LCMS Calculated for C₁₃H₁₃BrN₂O₂: 309.16, Observed=311.0.

Step 4: Synthesis of5-methoxy-3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenethyl)-pyrimidin-4(3H)-one,5

To a solution of 3-(4-bromophenethyl)-5-methoxypyrimidin-4(3H)-one, 4(100 mg, 0.32 mmol) and 4-(4-ethynylbenzyl) morpholine (130 mg, 0.65mmol) in dry DMF (2 mL) was added diisopropylamine (0.18 mL, 1.28 mmol)and triphenyl phosphine (8 mg, 0.03 mmol) at RT. The reaction wasdegassed by purging with N₂ for 15 minutes. Then, copper (I) iodide (4mg, 0.02 mmol) followed by PdCl₂(PPh₃)₂ (5 mg, 0.006 mmol) were added,and the reaction mixture was heated at 125° C. for 25 min in a microwavereactor. After completion of the reaction, the reaction mixture wasdiluted with water (10 mL), and the crude product was extracted withEtOAc (3×10 mL). The combined organic layer was washed with water (2×10mL) and finally with brine solution (10 mL). The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated to get crude product asa brown gummy syrup which is further purified by automated flash columnchromatography over silica gel (eluent: 5-7% MeOH in DCM) to obtain (50mg, 37%)5-methoxy-3-(4-((4(morpholinomethyl)-phenyl)ethynyl)phenethyl)pyrimidin-4(3H)-one,4 as an yellow solid. LCMS Calculated for C₂₆H₂₇N₃O₃: 429.52,Observed=429.2.

Step 5: Synthesis of5-hydroxy-3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenethyl)-pyrimidin-4(3H)-one,73

To a solution of 5-methoxy-3-(4-((4(morpholinomethyl)phenyl)ethynyl)phenethyl) pyrimidin-4(3H)-one, 4 (25 mg, 0.06 mmol) in dry pyridine (1mL) was added lithium iodide (40 mg, 0.29 mmol). The reaction mixturewas heated at 160° C. for 90 min in a microwave reactor. Aftercompletion of the reaction, the reaction mixture was concentrated todryness and the residue was dissolved in EtOAc (10 mL). The organiclayer was washed with water and brine solution, dried over anhydrousNa₂SO₄, filtered and concentrated to get crude product as a pale yellowsolid. The solid was further purified by trituration with diethyl etherto obtain (8 mg, 33%) compound 73 as an off-white solid. LCMS Calculatedfor C₂₅H₂₅N₃O₃: 415.49, Observed=416.0.

Synthesis of Compounds 74, 75, 76, 78, 86, 88, 97, 99 and 100

The synthetic scheme to prepare the amide backbones for compounds 74,75, 76, 78, 86, 88, 97, 99 and 100 is shown in FIG. 8.

Synthesis of Amides:

4-((4-aminophenyl)buta-1,3-diyn-1-yl)benzoic acid, 1 (0.3 g, 0.0014 mol)was taken in dry DMF (5 ml), R—NH₂ (0.0012 mol, 1.05 eq), DIPEA (0.296g, 0.00229 mol) and HATU (0.655 g, 0.00172 mol) respectively were addedand stirred the reaction mass for 3 h. After completion of the reaction,the reaction mixture was concentrated and added crushed ice. The solidsobtained were filtered and washed with water and dried under reducedpressure to get the respective amides. The amide backbones for compounds75, 76, 78, 99 and 86 were obtained by extraction and further columnpurification using 1-10% MeOH in DCM as eluent. The remaining compoundswere obtained by trituration using cold water. LC-MS and ¹H NMR confirmthe required product.

TABLE 2 Quantities and the purity of exemplary synthesized amidebackbones Compound ID Qty of No. R—NH₂ amide Yield Purification 97

0.352 g  94.5% trituration 74

0.36 g 85.7% trituration 75

0.37 g 90.2% Column Chromatography 76

0.40 g 93.2% Column chromatography 100

0.38 g 92.6% Trituration 78

0.39 g 78.7% Column chromatography 99

0.37 g 94.8% Column chromatography 86

0.35 g 96.4% Column chromatography 88

0.35 60.3% Trituration

TABLE 3 LCMS data of exemplary synthesized amide backbones Compound IDNo. Structure of the Amide LCMS 97

Calculated for C₂₁H₁₈N₂O₂ 330.39, Observed = 331.2 74

Calculated for C₂₄H₂₅N₃O 371.48, Observed = 372.5 75

Calculated for C₂₃H₂₃N₃O 357.46, Observed = 358.2 76

Calculated for C₂₄H₂₇N₃O 373.5, Observed = 374.5 100

Calculated for C₂₃H₂₃N₃O 357.46, Observed = 358.2 78

Calculated for C₂₆H₂₇N₃O₂ 413.52, Observed = 414.0 99

Calculated for C₂₂H₂₀N₂O₂ 344.41, Observed = 345.4 86

Calculated for C₂₀H₁₆N₂O₂ 316.36, Observed = 317.3 88

Calculated for C₁₉H₁₆N₂O₂ 304.3, Observed = 305.3 111

Calculated for C₂₇H₂₉N₃O₄ 459.55, Observed = 460.0Synthesis of Compound 104

The synthetic scheme to prepare compound 104 is shown in FIG. 9.

Step 1: Synthesis of diethyl2-(4-bromobenzyl)-2-(5,6-dimethoxypyrimidin-4-yl)malonate, 2

To a solution of Diethyl 2-(5,6-dimethoxypyrimidin-4-yl)malonate (0.2 g,0.67 mmol) in DMF (5 mL) Cs₂CO₃ (0.32 g, 1.0 mmol) and 4-bromo benzylbromide (0.16 g, 0.67 mmol) were added and stirred at 25° C. for 1 h.After completion of the reaction, the reaction mixture was diluted withwater and extracted with EtOAc (2*25 mL). The combined organic layerswere washed with brine solution, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography toget (0.21 g, 67%) of pure diethyl2-(4-bromobenzyl)-2-(5,6-dimethoxypyrimidin-4-yl)malonate, 2.UPLC=Calculated for C20H23BrN2O6 467.32, Observed=469.32

Step 2: Synthesis of 4-(4-bromophenethyl)-5,6-dimethoxypyrimidine,3

A solution of 2-(4-bromobenzyl)-2-(5,6-dimethoxypyrimidin-4-yl)malonate,2 (0.2 g, 0.74 mmol) in EtOH (3 mL) and H₂O (3 mL) was added NaOH (0.15g, 3.74 mmol) and stirred at 25° C. for 3 h. After completion of thereaction, the reaction mixture was diluted with water, acidified with1.5 N HCl and extracted with EtOAc (2*20 mL). The combined organiclayers were concentrated and obtained crude product was stirred in 2NHCl for 3 h. After completion of the reaction, the reaction mixture wasdiluted with water and extracted with EtOAc (2*10 mL). The combinedorganic layers were washed with brine solution, dried over Na₂SO₄,filtered and concentrated. The crude product was purified by columnchromatography to get (0.058 g, 44.6%) of pure diethyl4-(4-bromophenethyl)-5,6-dimethoxypyrimidine, 3. UPLC=Calculated forC14H15BrN202 323.19, Observed=325.2

Step 3: Synthesis of4-(4-((4-(2-(5,6-dimethoxypyrimidin-4-yl)ethyl)phenyl)ethynyl)benzyl)morpholine, 4

To solution of 4-(4-bromophenethyl)-5,6-dimethoxypyrimidine, 3 (0.05 g,0.14 mmol) in DMF (1 mL) were added 4-(4-ethynylbenzyl)morpholine (0.055g, 0.27 mmol), dipropylamine (0.057 g, 0.57 mmol) and triphenylphosphine(0.05 g, 0.0002 mol). The reaction mixture was purged with nitrogen for10 min, PdCl₂(PPh₃)₂ (4 mg, 0.014 mmol) was added followed by CuI (2 mg,0.08 mmol) and heated the reaction mixture in sealed tube for 3 h at100° C. After completion of the reaction, the reaction mixture wasdissolved in water and extracted with EtOAc (2*10 mL). The combinedorganic layers were washed with brine solution, dried over Na2SO4,filtered and concentrated and the crude product was purified by columnchromatography to get pure (0.03 g, 44%) of4-(4-((4-(2-(5,6-dimethoxypyrimidin-4-yl)ethyl)phenyl)ethynyl)benzyl)morpholine,4. LCMS=Calculated for C27H29N3O3 443.55, Observed=444.2

Step 4: Synthesis of5-hydroxy-6-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenethyl)pyrimidin-4(3H)-one, Compound 104

To a solution of4-(4-((4-(2-(5,6-dimethoxypyrimidin-4-yl)ethyl)phenyl)ethynyl)benzyl)morpholine,4 (0.03 g, 0.07 mmol), Lithium iodide (0.056 g, 0.42 mmol) was added andmicrowaved for 2 h at 170° C. After completion of the reaction pyridinewas removed and dissolved in EtOAc and the organic layer was washed withwater and brine solution. The organic layer was dried over Na2SO4,filtered and concentrated. The crude product was purified by prep TLC toget pure (5 mg, 17.8%)5-hydroxy-6-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenethyl)pyrimidin-4(3H)-one,compound 104. LCMS=Calculated for C25H25N3O3 415.49, Observed=416.0

Synthesis of Compound 105

The synthetic scheme to prepare compound 105 is shown in FIG. 10.

Step1: Synthesis of 4,5-dimethoxypyrimidine, 2

A solution of 4-chloro-5,6-dimethoxypyrimidine, 1 (5 g, 28.64 mmol) indry Methanol (100 mL) was hydrogenated at 1 atm H₂ gas pressure using Pd(10%) on carbon (1 g) as catalyst for 3 hours. After completion of thereaction, the reaction mixture was filtered through celite pad andconcentrated to dryness to get (4 g, 99%) of pure4,5-dimethoxypyrimidine, 2 as a white solid. UPLC=Calculated forC₆H₈N₂O₂ 140.14, Observed=141.1.

Step 2: Synthesis of 5-methoxypyrimidin-4(3H)-one hydrochloride, 3

A solution of 4,5-dimethoxypyrimidine, 2 (3 g, 21.41 mmol) in 6N HClsolution (30 mL) was heated at 100° C. for 16 h. After completion of thereaction, the reaction mixture was concentrated to dryness. Theoff-white residue was triturated with EtOAc (20 mL) and decanted to getpure (2.8 g, 80%) HCl salt of 5-methoxypyrimidin-4(3H)-one, 3 as anoff-white solid. LCMS=Calculated for C₅H₆N₂O₂ 126.12, Observed=127.0.

Step 3: Synthesis of 3-(4-bromophenethyl)-5-methoxypyrimidin-4(3H)-one,4

To a stirred solution of 5-methoxypyrimidin-4(3H)-one hydrochloride, 3(2 g, 12.3 mmol) and 4-bromophenethyl methanesulfonate (3.4 g, 12.3mmol) in dry DMF (40 mL) was added anhydrous K₂CO₃ (5.1 g). The reactionmixture was heated at 80° C. for 2 hours. After completion of thereaction, the reaction mixture was diluted with water (30 mL) and thecrude product was extracted with EtOAc (3×20 mL). The combined organiclayer was washed with water (2×20 mL) and finally with brine solution(20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated to get crude product as a pale yellow solid which isfurther purified by automated flash column chromatography over silicagel (eluent: 90-100% EtOAc in Pet ether) to obtain (800 mg, 21%)3-(4-bromophenethyl)-5-methoxypyrimidin-4(3H)-one, 4 as a white solid.LCMS=Calculated for C₁₃H₁₃BrN₂O₂ 309.16, Observed=311.0.

Step 4: Synthesis of5-methoxy-3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenethyl)pyrimidin-4(3H)-one,5

To a solution of 3-(4-bromophenethyl)-5-methoxypyrimidin-4(3H)-one, 4(100 mg, 0.32 mmol) and 4-(4-ethynylbenzyl) morpholine (130 mg, 0.65mmol) in dry DMF (2 mL) was added Dipropylamine (0.18 mL, 1.28 mmol) andTriphenyl phosphine (8 mg, 0.03 mmol) at RT. The reaction was degassedby purging with N₂ for 15 minutes. Then, Copper (I) iodide (4 mg, 0.02mmol) followed by PdCl₂(PPh₃)₂ (5 mg, 0.006 mmol) were added and thereaction mixture was heated at 125° C. for 25 min. in a microwavereactor. After completion of the reaction, the reaction mixture wasdiluted with water (10 mL) and the crude product was extracted withEtOAc (3×10 mL). The combined organic layer was washed with water (2×10mL) and finally with brine solution (10 mL). The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated to get crude product asa brown gummy syrup which is further purified by automated flash columnchromatography over silica gel (eluent: 5-7% MeOH in DCM) to obtain (50mg, 37%) 5-methoxy-3-(4-((4(morpholinomethyl)phenyl)ethynyl) phenethyl)pyrimidin-4(3H)-one, 4 as an yellow solid. LCMS=Calculated forC₂₆H₂₇N₃O₃ 429.52, Observed=429.2.

Step 5: Synthesis of5-hydroxy-3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenethyl)pyrimidin-4(3H)-one, Compound 105

To a solution of 5-methoxy-3-(4-((4(morpholinomethyl)phenyl)ethynyl)phenethyl) pyrimidin-4(3H)-one, 4 (25 mg, 0.06 mmol) in dry pyridine (1mL) was added lithium iodide (40 mg, 0.29 mmol). The reaction mixturewas heated at 160° C. for 90 min. in a microwave reactor. Aftercompletion of the reaction, the reaction mixture was concentrated todryness and the residue was dissolved in EtOAc (10 mL). The organiclayer was washed with water and brine solution, dried over anhydrousNa₂SO₄, filtered and concentrated to get crude product as a pale yellowsolid. It is further purified by trituration with diethyl ether toobtain (8 mg, 33%) FRG_046 as an off-white solid. LCMS=Calculated forC₂₅H₂₅N₃O₃ 415.49, Observed=416.0.

Synthesis of Compound 107 and 108

The synthetic scheme to prepare compounds 107 and 108 is shown in FIG.11.

Step 1: Ethyl 2-(5-methoxy-6-oxopyrimidin-1(6H)-yl) acetate (2)

To a solution of 5-methoxypyrimidin-4(3H)-one, 1(2 g, 0.0158 mol) inDMSO (10 mL), Cs₂CO₃ (15.4 g, 0.0475 mol) was added followed by ethylbromoacetate (3.97 g, 0.0237 mol) and stirred at 25° C. for 1 h. Aftercompletion of the reaction, the reaction mixture was diluted with waterand extracted with EtOAc. The aqueous layer was extracted with EtOAc(2×100 mL). The combined organic layers were washed with brine andorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to get (2.6 g, 81.2%) of 2. This was taken to thenext step without further purification.

UPLC=Calculated for C₉H₁₂N₂O₄ is 212.21, Observed=213.2 [M+H]⁺.

Step 2: Ethyl 3-(4-bromophenyl)-2-(5-methoxy-6-oxopyrimidin-1(6H)-yl)propanoate (3)

To a solution of 2 (2.5 g, 0.0117 mol) in THF (25 mL), LDA (2M in THF,7.06 mL, 0.014 mol) was added at −78° C. over a period of 10 min. Tothis cooled solution, 4-bromo benzylbromide (2.94 g, 0.0117 mol) wasadded and stirred for 1 h. After completion of the reaction, thereaction mixture was quenched with sat NH₄Cl solution and the reactionmixture was extracted with EtOAc (2×100 mL). The aqueous layer wasacidified with 1.5 N HCl (pH=5) and extracted with EtOAc. The combinedorganics was washed with brine and organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toget a mixture of 3 (1.4 g, 56%) and 4 (1.1 g, 23.9%).

LC_MS=Calculated for C₁₆H₁₇BrN₂O₄, 381.23, Observed=382.4 [M+H]⁺.

Step 3: 3-(4-bromophenyl)-2-(5-methoxy-6-oxopyrimidin-1(6H)-yl)propanoicacid (4)

To a solution of 3 (1.6 g, 0.004 mol) in EtOH (10 mL), water (10 mL) wasadded followed by NaOH (0.83 g, 0.0209 mol) and stirred the reactionmixture for 3 h. After completion of the reaction, the reaction mixturewas diluted with water and washed with diethyl ether. The aqueous layerwas acidified with 1.5 N HCl to pH=5 and extracted with EtOAc (2×30 mL).The combined organics was washed with brine and organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to get (1.3 g,87.8%) of 4. This was pure enough to be used in the next step withoutfurther purification.

UPLC=Calculated for C₁₄H₁₃BrN₂O₄, 353.17, Observed=354.3 [M+H]⁺.

Step 4:3-(4-bromophenyl)-N-methoxy-2-(5-methoxy-6-oxopyrimidin-1(6H)-yl)-N-methylpropanamide(5)

To a solution of 4 (1.5 g, 0.0042 mol) in DMF (15 mL),N,O-dimethylhydroxylamine.HCl (0.608 g, 0.0063 mol), HATU (2.3 g, 0.0063mol) and DIPEA (2.2 mL, 0.0127 mol) was added and stirred at 25° C. for1 h. After completion of the reaction, the reaction mixture was dilutedwith water and extracted with EtOAc (2×100 mL). The combined organicswas washed with brine and organic layer was dried over anhydrous Na₂SO₄,and concentrated under reduced pressure to get (1.3 g, 77.3%) of 5.UPLC=Calculated for C16H18BrN304 396.24, Observed=396.1 [M+H]⁺.

Step 5:3-(1-(4-bromophenyl)-3-oxobutan-2-yl)-5-methoxypyrimidin-4(3H)-one (6)

A solution of 5 (1 g, 0.0025 mol) in THF (20 mL) was cooled −20° C. Tothis was added methyl magnesium bromide (3M in Et₂O, 2.5 mL, 0.0075 mol)and stirred at 25° C. for 1 h. After completion of the reaction, thereaction mixture was quenched with sat. NH₄Cl, diluted with water andextracted with EtOAc (2×10 mL). The combined organics was washed withbrine and the organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel (230-400 mesh) to get (0.47 g,52.2.2%) of 6. LCMS=Calculated for C₁₅H₁BrN₂O₃ 351.20,Observed=351.1[M+H]⁺.

Step 6:5-methoxy-3-(1-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-3-oxobutan-2-yl)pyrimidin-4(3H)-one(7)

To solution of 6 (0.47 g, 0.00133 mol) in DMF (5 mL) was added4-(4-ethynylbenzyl)morpholine (0.807 g, 0.00401 mol), Et₃N (0.54 g,0.0053 mol) and triphenylphosphine (0.035 g, 0.00013 mol). The reactionmixture was purged with nitrogen for 10 min, PdCl₂(PPh₃)₂ (0.018g,0.000026 mol) was added followed by CuI (0.0152 g, 0.00008 mol) andthe reaction mixture was heated in a sealed tube for 3 h at 100° C.After completion of the reaction, the reaction mixture was dissolved inwater and extracted with EtOAc (2×30 mL). The combined organic layer waswashed with brine, dried over Na₂SO₄, and concentrated. The crudeproduct was purified by column chromatography on silica gel (230-400mesh) to get (0.31 g, 49.2%) 7.

LC_MS=Calculated for C₂₈H₂₉N₃O₄ 471.56, Observed=472.3 [M+H]⁺.

Step 7: 5-hydroxy-3-(1-(4-((4-(morpholinomethyl)phenyflethynyl)phenyl)-3-oxobutan-2-yl)pyrimidin-4(3H)-one, Compound 107

To a solution of 4 (0.26 g, 0.514 mmol) in pyridine (1 mL), Lithiumiodide (0.43 g, 0.0038 mol) was added and heated at 140° C. undermicrowave irradiation for 1 h. After completion of the reaction,pyridine was removed under reduced pressure and the crude product wasdissolved in water and extracted with EtOAc. The organic layer waswashed with water, brine and dried over Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by columnchromatography on silica gel (230-400 mesh) to afford Compund 107 (60mg, 24%) UPLC=Calculated for C₂₇H₂₇N₃O₄ 457.53, Observed=458.5 [M+H]⁺.

Step 8:5-hydroxy-3-(3-hydroxy-1-(4-((4(4-(morpholinomethyl)phenypethynyl)phenyl)butan-2-yl)pyrimidin-4(3H)-one,Compound 108

To a solution of hydroxy-3-(1-(4-((4-(morpholinomethyl)phenypethynyl)phenyl)-3-oxobutan-2-yl)pyrimidin-4(3H)-one (0.01 g, 0.02mmol) in methanol (1 mL) and THF (1 mL), Sodium borohydride (5 mg, 0.12mmol) was added and stirred at 25° C. for 10 min. After completion ofthe reaction, the reaction mixture was quenched with sat. NH₄Cl solutionand extracted with EtOAc. The organic layer was washed with brinesolution and dried over Na₂SO₄, filtered and concentrated under reducedpressure to get crude product. The crude product was triturated withdiethyl ether to afford Compund 108 (0.007 g, 70%). LCMS=Calculated forC₂₇H₂₉N₃O₄ 459.55, Observed=460.2 [M+H]⁺.

Synthesis of Compound 114

The synthetic scheme to prepare compound 114 is shown in FIG. 12.

Step 1: Synthesis of 3-methoxypyridin-2(1H)-one (2)

3-methoxypyridin-2(1H)-one (3 g, 0.0213 mol) was taken in conc. HCl (30mL) and heated at 80° C. for 5 h. After completion of the reaction, thereaction mixture was basified with sat NaHCO₃ and extracted with EtOAc.The organic layers were washed with brine solution and organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to get (2.5 g, 93.6%) of pure 3-methoxypyridin-2(1H)-one, 2UPLC=Calculated for C₆H₇NO₂ is 125.13, Observed=126.2.

Step 2: Synthesis of ethyl 2-(3-methoxy-2-oxopyridin-1(2H)-yl) acetate(3)

To a solution of 3-methoxypyridin-2(1H)-one, 2 (2.5 g, 0.02 mol) in DMSO(25 mL), Cs₂CO₃ (16.4 g, 0.05 mol), ethyl bromoacetate (5.01 g, 0.03mol) were added and stirred at 25° C. for 2 h. After completion of thereaction, the reaction mixture was diluted with water and extracted withEtOAc. The aqueous layer was extracted with EtOAc (2*100 mL). Thecombined organic layers were washed with brine solution and organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to get 3 (2.4 g, 57.1%). UPLC=Calculated for C₁₀H₁₃NO₄is 211.22, Observed=212.2.

Step 3: Synthesis of ethyl3-(4-bromophenyl)-2-(3-methoxy-2-oxopyridin-1(2H)-yl)propanoate (4)

To a solution of 3 (1.5 g, 0.007 mol) in THF (25 mL). LDA (2M in THF,5.3 mL, 0.0106 mol) was added at −78° C. for 10 min. To this 4-bromobenzyl bromide (1.9 g, 0.0078 mol) was added and stirred for 1 h. Aftercompletion of the reaction, the reaction mixture was quenched with satNH₄Cl solution and the reaction mixture was extracted with EtOAc (2*100mL). The aqueous layer was acidified with 1.5 N HCl (pH=5) and extractedwith EtOAc, combined organic layers were washed with brine solution andorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to get 4 (0.7 g, 25.9%) and 5 (0.6 g, 24%).LCMS=Calculated for C₁₇H₁₈BrNO₄, 380.24, Observed=381.4.

Step 4: Synthesis of3-(4-bromophenyl)-2-(3-methoxy-2-oxopyridin-1(2H)-yl)propanoic acid (5)

To a solution of ethyl3-(4-bromophenyl)-2-(3-methoxy-2-oxopyridin-1(2H)-yl)propanoate, 4 (0.7g, 0.0018 mol) in EtOH (10 mL), water (10 mL) NaOH (0.36 g, 0.0092 mol)was added and stirred the reaction mixture for 4 h. After completion ofthe reaction, the reaction mixture was diluted with water and extractedwith diethyl ether and layer was separated and the aqueous layer wasacidified with 1.5N HCl to (P^(H)=5) and extracted with EtOAc (2*10 mL).The combined organic layers were washed with brine solution and organiclayer was dried over Na₂SO₄, filtered and concentrated under reducedpressure to get (0.48 g, 75.1%) of pure3-(4-bromophenyl)-2-(3-methoxy-2-oxopyridin-1(2H)-yl)propanoic acid, 5.UPLC=Calculated for C₁₅H₁₄BrNO₄, 352.18, Observed=353.2.

Step 5: Synthesis of3-(4-bromophenyl)-N-methoxy-2-(3-methoxy-2-oxopyridin-1(2H)-yl)-N-methylpropanamide(6)

To a solution of 5 (0.3 g, 0.0008 mol) in DMF (5 mL), N,O-dimethylhydroxylamine HCl (0.078 g, 0.0012 mol), HATU (0.48 g, 0.0012 mol) andDIPEA (0.33 g, 0.0025 mol) was added and stirred at 25° C. for 2 h.After completion of the reaction, the reaction mixture was diluted withwater and extracted with EtOAc (2*100 mL). The combined organic layerswere washed with brine solution and organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toget 6 (0.28 g, 84.8%). UPLC=Calculated for C₁₇H₁₉BrN₂O₄ 395.25,Observed=396.24.

Step 6: Synthesis ofN-methoxy-2-(3-methoxy-2-oxopyridin-1(2H)-yl)-N-methyl-3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propanamide (7)

To a solution of 6 (0.28 g, 0.00070 mol) in DMF (2 mL) was added4-(4-ethynylbenzyl) morpholine (0.28 g, 0.0014 mol), Et₃N (0.28 g,0.0028 mol) and triphenylphosphine (0.018 g, 0.00007 mol). The reactionmixture was purged with nitrogen for 10 min, PdCl₂(PPh₃)₂ (0.0099 g,0.0000141 mol) was added followed by CuI (0.008 g, 0.000042 mol) andheated the reaction mixture in a sealed tube for 2 h at 100° C. Aftercompletion of the reaction, the reaction mixture was dissolved in waterand extracted with EtOAc (2*50 mL). The combined organic layers werewashed with brine solution, dried over Na₂SO₄, filtered and concentratedand the crude product was purified by column chromatography to get 7(0.25 g, 69.4%). LCMS=Calculated for C₃₀H₃₃N₃O₅, 515.61 Observed=516.2.

Step 7: Synthesis of2-(3-methoxy-2-oxopyridin-1(2H)-yl)-3-(4-((4-(morpholinomethyl) phenyl)ethynyl) phenyl)propanal (8)

To solution of 7 (0.3 g, 0.00048 mol) in THF (5 mL) at −78° C. was addedDiBAL-H (1M in THF, 0.16 mL, 0.0011 mol) and stirred the reaction for 1h at −78° C. After completion of the reaction, the reaction mixture wasquenched with saturated NH₄Cl solution and extracted with EtOAc. Theorganic layer was washed with brine solution and dried over Na₂SO₄,filtered and concentrated under reduced pressure to get 8 (0.022 g,80.7%). LCMS=Calculated for C₂₈H₂₈N₂O₄ 456.54, Observed=457.5.

Step 8: Synthesis of 1-(1-hydroxy-3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)propan-2-yl)-3-methoxypyridin-2(1H)-one (9)

To a solution of 8 (0.22 g, 0.48 mmol) in methanol (1 mL) Sodiumborohydride (36 mg, 0.96 mmol) was added and stirred at 25° C. for 10min. After completion of the reaction, the reaction mixture was quenchedwith sat. NH₄Cl solution and extracted with EtOAc. The organic layer waswashed with brine solution and dried over Na₂SO₄, filtered andconcentrated under reduced pressure to get 9 (21 mg, 95.2%).UPLC=Calculated for C₂₈H₃₀N₂O₄ 458.56, Observed=459.5.

Step 9: Synthesis of 3-hydroxy-1-(1-hydroxy-3-(4-((4-(morpholinomethyl)phenyl) ethynyl)phenyl)propan-2-yl)pyridin-2(1H)-one, Compound 114

To a solution of 9 (0.1 g, 0.218 mmol) in pyridine (1 mL), Lithiumiodide (0.173 g, 1.5 mmol) was added and irradiated under microwave for1 h at 140° C. After completion of the reaction, pyridine was removedand the crude product was dissolved in water and extracted with EtOAcand the organic layer was washed with water and brine solution and driedover Na₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel (5-10% ofmethanol in DCM) to get Compound 114 (0.016 g, 16.6%).

LCMS=Calculated for C₂₇H₂₈N₂O₄ 444.53, Observed=445.0.

Example 2 In Vitro Assays to Screen Compounds and MetalloproteinModulators Bacterial Susceptibility Testing

Minimal inhibitory concentrations (MIC) were determined by the brothmicrodilution method in accordance with the Clinical and LaboratoryStandards Institute (CLSI) guidelines. In brief, organism suspensionswere adjusted to a 0.5 McFarland standard to yield a final inoculumbetween 3×10⁵ and 7×10⁵ colony-forming units (CFU)/mL. Drug dilutionsand inocula were made in sterile, cation adjusted Mueller-Hinton Broth(Beckton Dickinson). An inoculum volume of 100 μL was added to wellscontaining 100 μL of broth with 2-fold serial dilutions of drug. Allinoculated microdilution trays were incubated in ambient air at 35° C.for 18-24 h. Following incubation, the lowest concentration of the drugthat prevented visible growth (OD600 nm<0.05) was recorded as the MIC.Performance of the assay was monitored by the use of laboratoryquality-control strains and levofloxacin, a compound with a defined MICspectrum, in accordance with CLSI guidelines.

TABLE 4 Exemplary in vitro assay data against select bacteria forcompounds in embodiments of the disclosure. P. E. coli E. coli S.aeruginosa ATCC E. coil E. coli delta to aureus P. 210 delta Compound25922- BW25113- imp IC ATCC aeruginosa mexAB- ID No. no FBS no FBSmutant mutant 29213 209 OprM 72 A A A A D D D 93 D D D D D D D 107 DN.D. D C N.D. N.D. N.D. 83 D D B C D D D 113 D N.D. D D N.D. N.D. N.D.91 D D D C C D D 78 D B A A D D D 92 D N.D. N.D. N.D. D D N.D. 70 D D BC C D D 94 D D D D D D D 71 D D D D D D D 90 D D B C D D D 106 D N.D. CA N.D. N.D. N.D. 84 D D D D D D D 103 D D D B D D D 87 B B B A D D D 100B B A A D D D 96 D D D D D D D 76 C B B A D D D 114 C N.D. B B N.D. N.D.N.D. 86 A A A A D D D 99 D B A A D D D 108 D N.D. C C N.D. N.D. N.D. 101D D D B D D D 82 D D B C D D D 98 B A B A D D D 102 C C C C D D C 74 C BB A D D D 89 D D C D C D D 105 C N.D. B B N.D. N.D. N.D. 95 D D C D D DD 104 C N.D. C B N.D. N.D. N.D. 97 B A A A D D D 75 C B B A D D D 112 CN.D. B A N.D. N.D. N.D. 88 A A A A D D D 73 C B B B D D D The MIC valuesin the table are as follows: A = less than 1 μg/mL; B = 1 to 8 μg/mL; C= greater than 8 to 32 μg/mL; D = greater than 32 μg/mL; and N.D. meansno data. FBS = fetal bovine serum.Inhibition Assay against Klebsiella pneumoniae LpxC

LpxC inhibition assays were performed using liquid chromatography withtandem mass spectrometry. Assays were performed, in duplicate, inopaque, 96-well microplates in a total assay volume of 50 μL. Theincubation mixture contained: LpxC (0.2 nM Kpn), 0.8 μMUDP-3-O—[(R)-3-hydroxymyristoyl]-N-acetyl-glucosamine, 40 mMBis-Tris/HCl buffer (pH 5.9), 5 mM sodium phosphate buffer(NaH₂PO₄/Na₂HPO₄, pH 7.0), 1 mM DTT, 0.1% (w/v) fatty-acid free BSA, 10%DMSO (v/v, with or without compound). The reactions were incubated at22° C. for 60 minutes (with mild shaking), then terminated by theaddition of 25 μL 0.25 N HCl. Samples were analyzed using a LC-MS systemto measure native LpxC substrate and reaction product. IC₅₀ analysis wasdone using GeneData Screener and a four parameter variable slopenormalized to controls. Test compounds were prepared as 8-pointdose-response curves (factor dilution 2) in triplicate, starting at 1 μMfinal concentration. Each assay plate included 6 wells used for the Z′factor calculation, 3 as a positive control for the assay and 3 as anegative control. The robustness was calculated as the median Z′ factorfor 5 plates. Chir-90, a well-known inhibitor of LpxC activity was usedas inhibitor control standard.

The dose response curves for a known LpxC inhibitor Chir-90 andexemplary compounds of the disclosure are shown in FIGS. 9-11.

The RZ′ factor obtained for this experiment (0.8324) indicates excellentassay quality in terms of signal dynamic range and data variation. TheIC₅₀ value of 0.47 nM calculated for the Chir-90 inhibitor is consistentwith previously reported values.

TABLE 5 Exemplary in vitro assay data against Klebsiella pneumoniae forcompounds in embodiments of the disclosure. Compound IC₅₀ ID No. (nM) 97C 98 C ChIR-090 A For the enzyme potency, IC₅₀ values against Klebsiellapneumoniae in the table are as follows: A = less than 1 nM; B = 1 toless than 10 nM; C = 10 to 100 nM; D = greater than 100 nM; and N/Dmeans no data.

Example 3 Treatment for Bacterial Infection

Human Clinical Trial of the Safety and/or Efficacy of Compounds forTreating Patients with cUTI, cIAI, HAP, or VAP

Objective: To compare the safety of administered composition comprisingcompound 72, 88, 86, 97, or 98.

Study Design: This will be an observational, cohort study from medicalchart review of adult hospitalized patients for each of the threeconditions of interest (complicated urinary tract infection (cUTI),complicated intra-abdominal infection (cIAI) and nosocomial pneumonia(NP) including hospital acquired pneumonia (HAP) andventilator-associated pneumonia (VAP)). For this study, the proposedpatient selection period extends for 12 months. Patients selected duringthis period will be followed from diagnosis (i.e., diagnosis of cUTI,cIAI or NP) until symptom resolution, discharge or 30-days postdischarge [based on data availability to assess readmission andoutpatient visits], death while hospitalized, loss to follow-up or theend of study period if not yet discharged from index hospitalization.

Study Population: Adult (18 years or older) patients with diagnosis ofat least one of the following conditions: urinary tract infection, intraabdominal infection, hospital acquired pneumonia, or ventilatorassociated pneumonia.

Phase I: Patients receive pharmaceutical compositions of compound 72,88, 86, 97, or 98, each day of a 28-day cycle. Doses of compound 72, 88,86, 97, or 98 may be held or modified for toxicity based on medicalassessment. Treatment repeats every 28 days in the absence ofunacceptable toxicity. Cohorts of 3-6 patients receive escalating dosesof the compound until the maximum tolerated dose (MTD) for the compoundis determined. The MTD is defined as the dose preceding that at which 2of 3 or 2 of 6 patients experience dose-limiting toxicity.

Phase II: Patients receive compound 72, 88, 86, 97, or 98 as in phase Iat the MTD determined in phase I. Treatment repeats every 4 weeks for2-6 courses in the absence of infection progression or unacceptabletoxicity. After completion of 2 courses of study therapy, patients whoachieve a complete or partial response may receive an additional 4courses. Patients who maintain stable infections for more than 2 monthsafter completion of 6 courses of study therapy may receive an additional6 courses at the time of infection progression, provided they meetoriginal eligibility criteria.

Testing: Tests that will be used to monitor the effectiveness of thetreated medical device include: physical exam, X-ray, urinalysis, bloodwork and other clinical laboratory methodologies used to detectpathogens in the patients.

Equivalents and Scope

It is, therefore, to be understood that the foregoing embodiments arepresented by way of example only and that, within the scope of theappended claims and equivalents thereto, the present teachings may bepracticed otherwise than as specifically described and claimed using nomore than routine experimentation. The present teachings are directed toeach individual feature and method described herein. In addition, anycombination of two or more such features and methods, if such featuresand methods are not mutually inconsistent, is included within the scopeof the present teachings. Such equivalents are intended to beencompassed by the scope of the following claims.

Where ranges are given, endpoints are included. Furthermore, it is to beunderstood that unless otherwise indicated or otherwise evident from thecontext and understanding of one of ordinary skill in the art, valuesthat are expressed as ranges can assume any specific value or subrangewithin the stated ranges in different embodiments of the disclosure, tothe tenth of the unit of the lower limit of the range, unless thecontext clearly dictates otherwise. All cited sources, for example,references, publications, databases, database entries, and art citedherein, are incorporated into this application by reference, even if notexpressly stated in the citation. In case of conflicting statements of acited source and the instant application, the statement in the instantapplication shall control.

What is claimed is:
 1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein: R₁ is H, C₁₋₆alkyl, or C₁₋₆ alkoxy; R₂ is H, C₁₋₆ alkyl, —N(R^(a))₂, —OH, or C₁₋₆alkoxy; R₃ is —NH₂, —OH, or —SH; Z is O or S; L₁ is a bond, —C₁₋₄alkylene-NR^(b)—, —C₁₋₄ alkylene-O—, —C₁₋₄ alkylene-S—, —C₁₋₄alkylene-S(O)₂—, —C(O)—, —C(O)NR^(b)—, —C(O)O—, or —NR^(b)C(O)—; L₂ is—(CR₄R₅)_(n)—C₀₋₃ alkylene-, —(CR₄R₅)_(n)—C₀₋₃ alkylene-CHOR^(c)—,—(CR₄R₅)_(n)—C₀₋₃ alkylene-C(NOH)—, —(CR₄R₅)_(n)—C₀₋₃ alkylene-C(O)—,—(CR₄R₅)_(n)—C₀₋₃ alkylene-C(O)NR₅—, —(CR₄R₅)_(n)—C₀₋₃ alkylene-NR₅—,—(CR₄R₅)_(n)—C₀₋₃ alkylene-NR₅C(O)—, —(CR₄R₅)_(n)—C₀₋₃alkylene-NR₅S(O)₂—, —(CR₄R₅)_(n)—C₀₋₃ alkylene-O—, —(CR₄R₅)_(n)—C₀₋₃alkylene-S(O)₂—, or —(CR₄R₅)_(n)—C₀₋₃ alkylene-S(O)₂NR₅—; each R₄ isindependently H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, —CN, —NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, —C(NR^(a))NR^(b)R^(c), —C(O)R^(a), —C(O)NR^(b)R^(c),—C(O)OR^(a), —NR^(b)R^(c), —NR^(a)C(NR^(d))NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(O)OR^(d),—NR^(a)S(O)R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)₂NR^(b)R^(c), —OR^(a), —OC(NR^(a))NR^(b)R^(c), —OC(O)R^(a),—OC(O)NR^(b)R^(c), —OC(O)OR^(a), —OS(O)R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂R^(a), —OS(O)₂NR^(b)R^(c), —P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d),—P(O)(OR^(a))(OR^(d)), —SR^(a), —S(O)R^(a), —S(O)NR^(b)R^(c),—S(O)₂R^(a), —S(O)₂NR^(b)R^(c), C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, and heterocyclyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclylsubstituent is optionally further substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —CN, —NO₂, —C(O)R^(a), —C(O)NR^(b)R^(c), —C(O)OR^(a),—NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(O)OR^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)₂NR^(b)R^(c), —OR^(a),—OC(O)R^(a), —OC(O)NR^(b)R^(c), —OC(O)OR^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a), and—S(O)₂NR^(b)R^(c); each R₅ is independently H, C₁₋₆ alkyl, —C₀₋₄alkylene-halogen, —C₀₋₄ alkylene-CN, —C₀₋₄ alkylene-NO₂, —C₀₋₄alkylene-C₂₋₄ alkenyl, —C₀₋₄ alkylene-C₂₋₄ alkynyl, —C₀₋₄alkylene-C(O)H, —C₀₋₄ alkylene-C(O)—C₁₋₆ alkyl, —C₀₋₄alkylene-C(O)NR^(b)R^(f), —C₀₋₄ alkylene-C(O)OR^(f), —C₀₋₄alkylene-N(R^(f))₂, —C₀₋₄ alkylene-NR^(b)C(O)R^(f), —C₀₋₄alkylene-OR^(f), —C₀₋₄ alkylene-S(O)₂R^(f), —C₀₋₄ alkylene-C₆₋₁₄ aryl,—C₁₋₄ alkylene-5- to 14-membered heteroaryl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃-C₈ cycloalkyl, C₂-C₇ heterocyclyl, C₆₋₁₄ aryl, or 5- to 14-memberedheteroaryl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃-C₈cycloalkyl, C₆₋₁₄ aryl, or 5- to 14-membered heteroaryl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, —CN, —NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, —C(NR^(a))NR^(b)R^(c), —C(O)R^(a), —C(O)NR^(b)R^(c),—C(O)OR^(a), —NR^(b)R^(c), —NR^(a)C(NR^(d))NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(O)OR^(d),—NR^(a)S(O)R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)₂NR^(b)R^(c), —OR^(a), —OC(NR^(a))NR^(b)R^(c), —OC(O)R^(a),—OC(O)NR^(b)R^(c), —OC(O)OR^(a), —OS(O)R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂R^(a), —OS(O)₂NR^(b)R^(c), —P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d),—P(O)(OR^(a))(OR^(d)), —SR^(a), —S(O)R^(a), —S(O)NR^(b)R^(c),—S(O)₂R^(a), —S(O)₂NR^(b)R^(c), C₃₋₁₀ cycloalkyl, heterocyclyl, C₆₋₁₄aryl, and heteroaryl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, C₆₋₁₄ aryl, or heteroaryl isoptionally further substituted with one or more substituentsindependently selected from the group consisting of halogen, —CN, —NO₂,—C(O)R^(a), —C(O)NR^(b)R^(c), —C(O)OR^(a), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(O)OR^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)₂NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)NR^(b)R^(c), —OC(O)OR^(a), —OS(O)NR^(b)R^(c), —OS(O)₂R^(a),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), and —S(O)₂NR^(b)R^(c); each R^(f) isindependently H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, —CN, —NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, —C(NR^(a))NR^(b)R^(c), —C(O)R^(a), —C(O)NR^(b)R^(c),—C(O)OR^(a), —NR^(b)R^(c), —NR^(a)C(NR^(d))NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(O)OR^(d),—NR^(a)S(O)R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)₂NR^(b)R^(c), —OR^(a), —OC(NR^(a))NR^(b)R^(c), —OC(O)R^(a),—OC(O)NR^(b)R^(c), —OC(O)OR^(a), —OS(O)R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂R^(a), —OS(O)₂NR^(b)R^(c), —P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d),—P(O)(OR^(a))(OR^(d)), —SR^(a), —S(O)R^(a), —S(O)NR^(b)R^(c),—S(O)₂R^(a), —S(O)₂NR^(b)R^(c), C₃₋₁₀ cycloalkyl, heterocyclyl, C₆₋₁₄aryl, and heteroaryl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, C₆₋₁₄ aryl, or heteroaryl isoptionally further substituted with one or more substituentsindependently selected from the group consisting of halogen, —CN, —NO₂,—C(O)R^(a), —C(O)NR^(b)R^(c), —C(O)OR^(a), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(O)OR^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)₂NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)NR^(b)R^(c), —OC(O)OR^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), and —S(O)₂NR^(b)R^(c); L₃ is —C₂₋₆alkenylene- or —C₂₋₆ alkynylene-; L₄ is —C₁₋₄ alkylene-, —C(O)—,—C(O)NR^(e)—, —C(O)O—, or —NR^(e)C(O)—; G₁ is —C₆₋₁₄ arylene- or -5- to14-membered heteroarylene-; G₂ is —C₆₋₁₄ arylene- or -5- to 14-memberedheteroarylene-; G₃ is H, alkyl, alkenyl, alkynyl, alkoxy, C₃₋₇cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₃₋₁₀ heterocycloalkylene-C₁₋₄alkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy,C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, aryl, or heteroaryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, —CN, —NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, —C(NR^(a))NR^(b)R^(c), —C(O)R^(a),—C(O)NR^(b)R^(c), —C(O)OR^(a), —NR^(b)R^(c),—NR^(a)C(NR^(d))NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(O)OR^(d), —NR^(a)S(O)R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)₂NR^(b)R^(c), —OR^(a),—OC(NR^(a))NR^(b)R^(c), —OC(O)R^(a), —OC(O)NR^(b)R^(c), —OC(O)OR^(a),—OS(O)R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂R^(a), —OS(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)NR^(b)R^(c), —S(O)₂R^(a), —S(O)₂NR^(b)R^(c), C₃₋₁₀cycloalkyl, heterocyclyl, C₆₋₁₄ aryl, and heteroaryl, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, C₆₋₁₄aryl, or heteroaryl is optionally further substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —CN, —NO₂, —C(O)R^(a), —C(O)NR^(b)R^(c), —C(O)OR^(a),—NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(O)OR^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)₂NR^(b)R^(c), —OR^(a),—OC(O)R^(a), —OC(O)NR^(b)R^(c), —OC(O)OR^(a), —OS(O)NR^(b)R^(c),—OS(O)₂R^(a), —SR^(a), —S(O)R^(a), —S(O)₂R^(a), and —S(O)₂NR^(b)R^(c);each R^(a) is independently H or C₁₋₆ alkyl; each R^(b) is independentlyH or C₁₋₆ alkyl; each R^(c) is independently H or C₁₋₆ alkyl; each R^(d)is independently H or C₁₋₆ alkyl; R^(e) is H or C₁₋₆ alkyl; and n is 1or
 2. 2. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein L₁ is a bond, —C₁₋₄ alkylene-NR^(b)—, —C₁₋₄alkylene-O—, —C₁₋₄ alkylene-S—, or —C₁₋₄ alkylene-S(O)₂—.
 3. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein L₂ is —(CR₄R₅)_(n)—C₀₋₃ alkylene-, —(CR₄R₅)_(n)—C₀₋₃alkylene-CHOR^(c)—, —(CR₄R₅)_(n)—C₀₋₃ alkylene-C(O)—, —(CR₄R₅)_(n)—C₀₋₃alkylene-C(O)NR₅—, —(CR₄R₅)_(n)—C₀₋₃ alkylene-NR₅—, —(CR₄R₅)_(n)—C₀₋₃alkylene-NR₅C(O)—, —(CR₄R₅)_(n)—C₀₋₃ alkylene-O—, or —(CR₄R₅)_(n)—C₀₋₃alkylene-S(O)₂—.
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein L₂ is —(CR₄R₅)_(n)—C₀₋₃ alkylene- or—(CR₄R₅)_(n)—C₀₋₃ alkylene CHOR^(c).
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein L₃ is —C₂₋₆alkynylene-.
 6. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R₅ is independently —C₁₋₄alkylene-N(R^(f))₂, —C₁₋₄ alkylene-OR^(f), —C₁₋₄ alkylene-S(O)₂R^(f),—C₁₋₄ alkylene-C₆₋₁₄ aryl, or —C₁₋₄ alkylene-5- to 14-memberedheteroaryl.
 7. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein: each R₄ is independently H; and each R₅ isindependently H, —C₁₋₆ alkyl, or —C₀₋₄ alkylene-OR^(f).
 8. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein: eachR₄ is independently H; and each R₅ is independently H, —C₀₋₄alkylene-CN, —C₀₋₄ alkylene-C(O)—C₁₋₆ alkyl, or —C₀₋₄ alkylene-OR^(f).9. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein: each R₄ is independently H; and each R₅ isindependently H, —C₁₋₄ alkylene-C(O)NR′R^(f), —C₁₋₄ alkylene-N(R^(f))₂,—C₁₋₄ alkylene-NR^(b)C(O)R^(f), or —C₁₋₄ alkylene-OR^(f).
 10. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: R₁ is H or C₁₋₆ alkyl; R₂ is H, C₁₋₆ alkyl, —OH, or C₁₋₆alkoxy; R₃ is —OH; Z is O; L₁ is a bond, —C₁₋₄ alkylene-NR^(b)—, —C₁₋₄alkylene-S(O)₂—, —C(O)—, —C(O)NR^(b)—, —C(O)O—, or —NR^(b)C(O)—; L₂ is—(CR₄R₅)_(n)—C₀₋₃ alkylene-, —(CR₄R₅)_(n)—C₀₋₃ alkylene-CHOR^(c)—,—(CR₄R₅)_(n)—C₀₋₃ alkylene-C(NOH)—, —(CR₄R₅)_(n)—C₀₋₃ alkylene-C(O)—,—(CR₄R₅)_(n)—C₀₋₃ alkylene-C(O)NR₅—, —(CR₄R₅)_(n)—C₀₋₃ alkylene-NR₅—,—(CR₄R₅)_(n)—C₀₋₃ alkylene-NR₅C(O)—, or —(CR₄R₅)_(n)—C₀₋₃ alkylene-O—;each R₅ is independently H, C₁₋₆ alkyl, —C₁₋₄ alkylene-N(R^(f))₂, —C₁₋₄alkylene-OR^(f), or —C₁₋₄ alkylene-S(O)₂R^(f); L₃ is —C₂₋₆ alkynylene-;G₁ is —C₆ arylene- or -5- to 6-membered heteroarylene-; G₂ is —C₆arylene- or -5- to 6-membered heteroarylene-; and G₃ is H, C₁₋₄alkylene-O—C₁₋₄ alkyl, alkoxy, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl,C₃₋₁₀ heterocycloalkylene-C₁₋₄ alkyl, C₃₋₁₀ heterocycloalkylene-O—C₁₋₄alkyl, C₆₋₁₄ aryl, or 5- to 14-membered heteroaryl, wherein the C₁₋₄alkyl, alkoxy, C₃₋₇ cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, orheteroaryl is optionally substituted.
 11. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: R₁ is H or C₁₋₆alkyl; R₂ is H or C₁₋₆ alkyl; R₃ is —OH; Z is O; L₁ is a bond, —C(O)—,—C(O)NR^(b)—, —C(O)O—, or —NR^(b)C(O)—; L₂ is —[C(R₄)(R₅)]_(n)—C₀₋₃alkylene-; each R₅ is independently H or C₁₋₆ alkyl; L₃ is —C₂₋₆alkynylene-; L₄ is —C₁₋₄ alkylene- or —C(O)—; G₁ is —C₆ arylene- or -5-to 6-membered heteroarylene-; G₂ is —C₆ arylene- or -5- to 6-memberedheteroarylene-; and G₃ is H, C₁₋₄ alkylene-O—C₁₋₄ alkyl, alkoxy, C₃₋₇cycloalkyl, C₃₋₁₀ heterocycloalkyl, C₃₋₁₀ heterocycloalkylene-C₁₋₄alkyl, C₃₋₁₀ heterocycloalkylene-O—C₁₋₄ alkyl, C₆₋₁₄ aryl, or 5- to14-membered heteroaryl, wherein the C₁₋₄ alkyl, alkoxy, C₃₋₇ cycloalkyl,C₃₋₁₀ heterocycloalkyl, C₆₋₁₄ aryl, or heteroaryl is optionallysubstituted; and n is
 1. 12. The compound of claim 1, wherein thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 14. A method for modulating theactivity of UDP-{3-O—[(R)-3-hydroxymyristoyl]}-N-acetylglucosaminedeacetylase in a subject, comprising administering to the subject inneed thereof a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof.
 15. A method fortreating a gram-negative bacterial infection in a subject, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 16. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.